Translational Neuroimaging || Neuroimaging Approaches to the Understanding of Depression and the Identification of Novel Antidepressants

C H A P T E R

12

Neuroimaging Approaches to theUnderstanding of Depression and

the Identification of NovelAntidepressants

Poornima Kumar 1, Catherine J. Harmer 2, Colin T. Dourish 3

1Center for Depression, Anxiety and Stress Research, McLean Hospital/Harvard

Medical School, Belmont, MA 02478, USA2University Department of Psychiatry, University of Oxford, Warneford Hospital,

Headington, Oxford OX3 7JX, United Kingdom3P1vital Ltd., Department of Psychiatry, University of Oxford, Warneford Hospital,

Headington, Oxford OX3 7JX, United Kingdom

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1.0. Introduction 3
45
2.0. Imaging Techniques 3
462.1. MRI 346 2.2. fMRI 346 2.3. PET 347 2.4. Electroencephalography 347 2.5. Magnetoencephalography 348 2.6. MRS 349
2.6.1. N-Acetylaspartate
349
2.6.2. Choline
349
2.6.3. Creatine
349
2.6.4. Myo-Inositol
350
2.6.5. Glutamine and

Glutamate
350
343ranslational Neuroimaging

ttp://dx.doi.org/10.1016/B978-0-12-386945-6.00012-3

2.6.6. GABA
350
2.7. Arterial Spin Labeling 350
2.8. Diffusion Tensor Imaging 351
3.0. Characterization of Disease Stateand Progression 3
513.1. Structural Changes 351
3.1.1. Volumetric

Measurements
351
3.1.2. White Matter

Abnormalities
354
3.2. Functional Changes 354
3.2.1. Depressed Mood and
Negative Bias
354
� 2013 Elsevier Inc. All rights reserved.

http://dx.doi.org/10.1016/B978-0-12-386945-6.00012-3

12. NEUROIMAGING AND MAJOR DEPRESSIVE DISORDER344

3.2.2. Anhedonia and

Hypersensitivity to

Negative Feedback
356
3.2.3. Impaired Learning and

Memory
358
3.2.4. Impaired Executive

Function
358
3.2.5. Impaired Social

Cognition
359
3.3. Resting State Abnormalities 361
3.3.1. fMRI 361
3.3.2. Electroencephalography
362
3.3.3. Perfusion Arterial Spin

Labeling
362
3.3.4. PET
363
3.3.5. Receptor Binding
363
3.4. Biochemical Alterations in MajorDepressive Disorder ChangesDetected Through 1H-MRS 364
3.4.1. N-Acetylaspartate 364
3.4.2. Choline Compounds
365
3.4.3. Myo-Inositol
365
3.4.4. GABA
365
3.4.5. Glutamate
366
4.0. Characterization of TherapeuticManipulations 3
664.1. Pharmacological Studies 366
4.1.1. Negative Bias
367
4.1.2. Social Cognition
367
4.2. PET 368
4.3. Glutamate 368
5.0. Use of Neuroimaging in BiomarkerIdentification and Early DrugDiscovery 3
69
5.1. Role of Various NeuroimagingModalities in Drug Development forDepression 37
0 5.1.1. PET 370
5.1.2. fMRI
370
371
5.1.4. Biomarkers from MRS
373
5.2. Identification of Specific RegionalBiomarkers in the Brain UsingFMRI, PET, andElectroencephalography 374
5.2.1. Amygdala 374
5.2.2. Hypoactive Prefrontal

Cortex
374
5.2.3. Subgenual Cingulate

Cortex
374
6.0. Behavioral Correlates and Use ofNeuroimaging Biomarkers inModels of Depression 3
756.1. Theories of Human Major
Depressive Disorder 375
6.1.1. Monoamine Hypothesis 375
6.1.2. Glutamate Hypothesis
378
6.1.3. Neurotropic Theories
379
6.1.4. Neurodevelopmental

TheoriesdGenetic

Polymorphisms
381
7.0. Reciprocal Nature of NeuroimagingResults in Animal and HumanModels of Depression 3
847.1. Advances in Developing Drugs for
Depression Through the Use ofNeuroimaging 384

8.0. Summary and Future Prospects 3
85
SummaryThere is a significant medical need for new drug therapies to treat major depressive disorder (MDD).However, the poor predictive validity of preclinical methods available to detect the potential efficacy of novelcompounds and a lack of common endpoints between preclinical and clinical measures have proved to bemajor limitations in drug development for MDD. Neuroimaging studies have provided important insights

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1.0. INTRODUCTION 345

into our understanding of MDD. Many imaging methods, such as functional magnetic resonance imaging(fMRI) and positron emission tomography (PET), can be applied in animal species used for preclinicalresearch, in addition to being widely used in clinical studies. Consequently, neuroimaging approaches arebecoming increasingly valuable for drug discovery and development, and the potential translation ofpreclinical promise to clinical therapeutic benefit.Neuroimaging methods that have been routinely used to study MDD include MRI, fMRI, magneticresonance spectroscopy (MRS), PET, electroencephalography, and, more recently, magneto-encephalography. In behavioral and cognitive tasks MDD is associated with negative bias, impairedlearning and memory, cognition, blunted reward responsiveness, hypersensitivity to punishment, andimpaired social cognition. Imaging studies using MRI, fMRI, MRS, and PET have identified a number ofbrain regions that are functionally, neurochemically, and structurally abnormal in MDD and which areimplicated in mediating these cognitive deficits. Potential biomarkers for MDD that have been iden-tified using different imaging methods include hyperactive amygdala, corticolimbic dysfunction,hyperactive subgenual cingulate, and frontal asymmetry.The prevalent hypothesis during the past 30years of drug discovery and development for MDD has been themonoamine hypothesis. However, the discovery of the rapid-onset antidepressant properties of the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, together with new imaging approaches to drug discoveryhave directed interest toward the brain glutamate system as a promising target for new treatments for MDD.

1.0. INTRODUCTION

Major depressive disorder (MDD) is a leading cause of disability and produces a greaterdecrement in health than other common chronic diseases, such as angina, arthritis, asthma,and diabetes. MDD is the most common psychiatric disorder worldwide and is associatedwith a high level of disability and impairment in the quality of life.1 Current pharmacologicaltherapies target the brain monoamine systems, but approximately only one-third of patientsachieve remission with the first medication prescribed and the slow clinical onset of theirantidepressant action means that the detection of response or nonresponse requires at least4e6weeks of drug treatment. In addition, many patients suffer from significant side effectsand may suffer a relapse during long-term treatment.2,3 Hence, there is a significant need fornew therapies to treat MDD, but their emergence has been limited at least in part by the poorpredictive validity of the preclinical methods available to detect the potential efficacy ofnovel compounds prior to expensive large-scale clinical trials in patients.4 The lack ofcommon endpoints between preclinical and clinical measures has also proven to be a majorlimitation in drug development for MDD.i

Experimental or translational medicine models in humans, particularly those that incorpo-rate neuroimaging, may have the potential to overcome some of these difficulties by bothincreasing our understanding of brain function in MDD and their use in compound efficacyscreening to identify improved drug therapies.

r further discussion on the topic of the predictive validity of pre-clinical methods in the discovery and

velopment of drugs with clinical efficacy for the treatment of MDD and the lack of common pre-clinical

clinical endpoints, please refer to McArthur, R. and F. Borsini (2006). “Animal models of depression in

g discovery: A historical perspective.” Pharmacol Biochem Behav 84(3): 436e452 and McArthur, R. A.

F. Borsini (2008). What Do You Mean By “Translational Research”? An Enquiry through Animal and

nslational Models for CNS Drug Discovery: Psychiatric Disorders. Animal and Translational Models for

S Drug Discovery: Psychiatric Disorders. San Diego, CA, Academic Press. 1: xvii-xxxviii.


2.0. IMAGING TECHNIQUES

Neuroimaging tools currently being used to understand the pathophysiological mecha-nisms of MDD can be classified into structural, functional, and chemical methods. Structuralimagingmethods include the use of structural magnetic resonance imaging (sMRI) and diffu-sion tensor imaging (DTI). Functional imaging approaches include positron emission tomog-raphy (PET), functional magnetic resonance imaging (fMRI), perfusion imaging usingarterial spin labeling (ASL) methods, electroencephalography (EEG), and magnetoencepha-lography (MEG). Chemical imaging methods include magnetic resonance spectroscopy(MRS). A brief introduction to these methods will be provided in this section.ii

2.1. MRI

In 1971, Damadian showed that the nuclear magnetic relaxation times of tissues andtumors differed, thus motivating scientists to consider nuclear magnetic resonance (NMR)for the detection of disease.5 A few years later, in 1977, Damadian developed field-focusingNMR and was the first to perform a full human body scan to diagnose cancer.6 It took almost5 h to collect a single image. NMR was later renamed MRI because the term nuclear was off-putting for patients. Paul Lauterbur and Peter Mansfield were awarded the Nobel Prize inPhysiology or Medicine in 2003 for their discoveries concerning MRI.

AnMRImachine uses a powerfulmagnetic field to align themagnetization of atomic nuclei(mainly hydrogen) in the body and radio frequency fields to alter the alignment of thismagne-tization systematically. This causes the nuclei to produce a rotating magnetic field detectableby the scanner and this information is recorded to construct an image of the scanned area of thebody.7Magnetic field gradients cause nuclei at different locations to rotate at different speeds.By using gradients in three different directions three-dimensional (3D) volumes can beobtained. One advantage of an MRI scan is that it is harmless to the patient. It uses strongmagnetic fields and nonionizing radiation in the radio frequency range, unlike computedtomography scans and traditional X-rays, which both use ionizing radiation.

sMRI scans are usually T1-weighted scans that differentiate fat from water (water beingdarker and fat brighter), and this provides information on (ab)normal anatomy. sMRI canbe important for detecting the affected structure in any psychiatric disorder, as volumes ofspecific brain regions can be calculated and gray matter abnormalities determined.

2.2. fMRI

Functional magnetic resonance imaging is an MRI procedure that measures brain activityby detecting changes in blood flow. Since the 1980s, it has been known that changes in blood

iiFor further detailed discussion of neuroimaging modalities, please refer to Wise in Chapter 1, Neuro-

imaging Modalities: Description, Comparisons, Strengths, and Weaknesses; Brown in Chapter 2, Magnetic

Resonance Imaging as a Tool for Modeling Drug Treatment of CNS Disorders: Strengths and Weaknesses;

Novak and Einstein in Chapter 4, Structural Magnetic Resonance Imaging as a Biomarker for the Diagnosis,

Progression, and Treatment of Alzheimer Disease; and Schmidt et al. in Chapter 5, Positron Emission

Tomography in Alzheimer Disease: Diagnosis and Use as Biomarker Endpoints, in this volume.

2.0. IMAGING TECHNIQUES 347

flow and oxygenation in the brain (collectively known as hemodynamics) are closely linkedto neural activity.8 When neurons become active at rest or during a task, local blood flow tothose brain regions increases and oxygen-rich (oxygenated) blood displaces oxygen-depleted(deoxygenated) blood around 2 s later. This rises to a peak over 4e6 s, before falling back tothe original level (and typically undershooting slightly). Oxygen is carried by the hemo-globin molecule in red blood cells. Deoxygenated hemoglobin (dHb) is more magnetic(paramagnetic) than oxygenated hemoglobin (Hb), which is virtually nonmagnetic (diamag-netic). This difference leads to an improved magnetic resonance (MR) signal, since thenonmagnetic blood causes less interference with the magnetic MR signal. This improvementcan be mapped to infer which brain regions are active at a particular time.9

The seminal fMRI work was first carried out in rodents.10 Subsequently, in 1992, threegroups independently obtained results in humans with the blood oxygenation level depen-dent (BOLD) mechanism,11e13 setting off a flood of fMRI publications that have been appear-ing in scientific journals ever since. Research over the last decade has established that BOLDcontrast depends not only on blood oxygenation but also on cerebral blood flow (CBF) andvolume (CBV), a complex response controlled by several parameters. Logothetis andcolleagues showed that the BOLD response is more closely related to local synaptic activitythan the spiking of single or multiple neurons14 and that changes in the local field potentialsare more closely related to the evolution of the BOLD signal than to changes in the spikingactivity of single or multiple neurons.15

Given that brain-based endophenotypes may hold relatively greater promise as predictorsof disease manifestation and progression, owing to the closer association between suchmeasures and the genetic and environmental causes of psychiatric illness than observablebehavior, functional brain imaging is a powerful tool for evaluating potential markers ofdisease vulnerability.16

2.3. PET

PET is a nuclear medicine imaging technique that produces a 3D image of functionalprocesses in the body, by detecting pairs of g rays emitted indirectly by a positron-emittingradionuclide (tracer), which is introduced into the body on a biologically active molecule.Three-dimensional images of tracer concentrations within the body are then constructedby computer analysis. If the biologically active molecule chosen for PET is fluorodeoxyglu-cose (FDG), an analogue of glucose, the concentrations of tracer imaged indicates tissuemetabolic activity, in terms of regional glucose uptake. This method has been used tomeasure CBF to the brain regions in MDD.

Radiotracers that are specific ligands for receptor subtypes that have been implicatedin MDD have also been developed for PET, such as 11C-McN 5652 and 11C-DASB[3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile] for serotonin trans-porters and 11C-WAY-100635 for serotonin 5-HT1A receptors.

2.4. Electroencephalography

Since the first human electroencephalogram was recorded in 1924 and reported in 1929by Hans Berger, the German physiologist and psychiatrist, EEG has been used extensively


in the clinical diagnosis of epilepsy and sleep disorders. It has become popular overdecades in psychiatric research, specifically into depression. EEG is the recording of spon-taneous electrical activity over a short period of time, usually 20e40 min, from multipleelectrodes placed on the scalp. EEG measures voltage fluctuations resulting from ioniccurrent flows within the neurons of the brain. As the electrical potentials generated bysingle neurons are too small to be detected by EEG, EEG activity refers to the summationof the synchronous activity of thousands or millions of neurons that have similar spatialorientations. Voltage fields fall off with the square of distance, and therefore activityfrom deep sources is more difficult to detect than currents near the skull. EEG measuresneuronal electrical activity directly, while other methods record changes in blood flow[e.g. single photon emission computed tomography (SPECT) and fMRI] or metabolicactivity [PET and near-infrared spectroscopy (NIRS)], which are indirect measures of thebrain’s electrical activity. EEG has higher temporal resolution (milliseconds), but signifi-cantly lower spatial resolution, compared to fMRI.

Normal rhythmic EEG activity is divided into bands by frequency. The relative distributionof frequency bands varieswith age, and is influenced by the level of alertness, medication, andbrain pathology. Beta waves (frequency range, 12e30 Hz) are associated with normal wakingconsciousness and low betawaves are usually observedwith active, busy, or anxious thinkingand active concentration; alphawaves (8e12 Hz) emerge during relaxation andwhen the eyesare closed, and attenuate with eye opening or mental exertion; theta waves (4e7Hz) arepresent in drowsiness or meditation; and delta waves (up to 4 Hz) are present in healthyadults during slow-wave sleep. EEG signals are also described in terms of the power of theelectrical signal. EEG results are sometimes reported in terms of absolute and relative power.Absolute power is the amount of power in an EEG frequency band at a given electrode,measured in microvolts squared (mV2). Relative power is the percentage of power containedin a frequency band in relation to the total power across the entire spectrum. EEG asymmetriesrepresent the differences in EEG activity between the left and right hemispheres.17

Initially, most EEG recordings reported were resting state EEGs (spontaneous potentials).Amore recently reported version of spontaneous EEG is quantitative electroencephalography(or QEEG), which involves computerized spectral analysis of EEG signals, thus providinginformation that cannot be extracted through visual inspection of EEG recordings alone.

Simultaneous EEG-fMRI procedures are becoming popular in the study of psychiatricdisorders. Their advantage is that high temporal resolution data can be recorded at thesame time as high spatial resolution data, thereby enabling the identification of commonneuronal generators by removing possible intersession biases and allowing the study ofspontaneous brain activity. For example, it has been shown that spontaneous fluctuationsof EEG alpha power in a resting state covaried with fluctuations of the BOLD resting statesignal. Using single trial amplitude of different event-related potential (ERP) componentsas predictors of BOLD changes, it is possible to identify corresponding brain regions usingfMRI at a timescale close to that of EEG.18

2.5. Magnetoencephalography

MEG is a noninvasive method of recording neural activity. It is a neurophysiological tech-nique that records the magnetic sources generated from simultaneous firing of groups of

2.0. IMAGING TECHNIQUES 349

pyramidal cells. MEG measures neuronal activity directly and thus records real-time activitywith millisecond resolution.19

In 1968, Cohen made the first recordings of neural activity with a single magnetometer.20

With the introduction of superconducting quantum interference devices (SQUIDs), the sensi-tivity of MEG has been greatly increased. MEG uses several hundred sensors, making itpossible to record the magnetic output with high temporal (< 1ms) and spatial (1e5mm)resolution, thus making it an invaluable tool in neurophysiological research.

One of themost exciting areas of research usingMEG is the analysis of temporal correlationsor coherence. MEG data provide an opportunity to examine the synchrony or coherence ofneural oscillations at different frequency bands (alpha, beta, gamma, and theta) within a partic-ular brain region or across regions.19 This can be achieved during rest or by evoking a responsethrough the presentation of stimuli at specific time periods. Many psychiatric disorders havebeen shown to have abnormal synchronicity. MEG signals are thought to arise from postsyn-aptic current flow in apical dendrites and are proposed to correspond closely toBOLDsignals.21

2.6. MRS

MRS is the only currently available imaging technique that allows real-time in vivo quan-tification of brainmetabolites in localized brain regions. Among the several nuclei assessed inMRS examinations, proton (1H-)MRS is the most commonly used in investigations of theneurochemical basis of MDD.22 This is due to the high natural abundance of hydrogenprotons and their high absolute sensitivity to magnetic manipulation. The types of metabo-lites that are commonly studied in MDD include choline-containing compounds, creatine,myo-inositol, N-acetylaspartate (NAA), g-aminobutyric acid (GABA), and glutamate.


NAA is the most prominent resonance (peak), with its major resonance occurring at2.02 parts per million (ppm). NAA is considered a marker for neuronal and axonal integrity,and is associated with formation and maintenance of myelin. A decrease in NAA levels isa sign of neuronal loss or damage. A gradual and progressive increase in NAA is seen duringbrain development and maturation in infancy.23

2.6.2. Choline

Choline (Cho) is seen as a peak at 3.2 ppm and is an essential precursor of the neurotrans-mitter acetylcholine.23 It represents the sum of choline-containing compounds such as glyc-erophosphocholine, phosphatidylcholine, and phosphocholine. Choline therefore representsthe constituents of the cell membrane and is a marker for membrane turnover.24 The Chopeak has received considerable attention in MDD on the basis of theories of cholinergichyperactivity in depression.25

2.6.3. Creatine

Creatine (Cr), including phosphocreatine (PCr), is displayed at 3.0 ppm and is amarker forbrain energy metabolism. It is stable and commonly used as an internal standard. However,variations in Cr levels do occur, as in the gradual loss of Cr, together with other major metab-olites, in tissue death or necrosis.23


2.6.4. Myo-Inositol

Myo-inositol (mI) is a sugar involved in the regulation of neuronal osmolarity. A mI signalat 3.56 ppm represents predominantly myo-inositol with minor contributions (< 5%) fromglycine and inositol-1-phosphate.23

2.6.5. Glutamine and Glutamate

Glutamine (Gln) and glutamate (Glu) are detectable as multiple resonances between 2.2and 2.4 ppm when using a short echo time (TE). The identification of glutamate usingMRS is technically challenging, as the Glu spectrum overlaps with a number of other neuro-chemicals, primarily glutamine. Stronger magnetic fields and advanced imaging techniquescan enable isolation of the glutamate signal; however early MRS studies reported combinedGlu and Gln peaks as glutamix (Glx).26 The first clinical report of MRS being used to examineGlx in depression was of a cancer patient who had recurrent suicidal ideation and depressivesymptoms with chemotherapy. In this individual, Glx was reduced in cerebral whitematter.27

2.6.6. GABA

GABA is a ubiquitous inhibitory neurotransmitter found almost exclusively in the centralnervous system (CNS), with concentrations at least 1000 times greater than that of mono-amines. It regulates neuronal excitability through inhibitory feedback loops and controlsmuscle tone peripherally. Extensive clinical and preclinical investigations indicate that theamygdala, hippocampus, hypothalamus, midbrain, prefrontal cortex (PFC), and tectumare rich in GABAergic neurons.28 GABAergic interneurons selectively attenuate the firingof other neurons in the cortex through cortical inhibition. Cortical inhibition has severalimportant physiological functions including learning, memory, and sensory gating. Sensorygating is the inhibition that reduces aberrant neuronal firing, filters spurious information,and improves the signal-to-noise ratio. Levesque and colleagues proposed that this latterfunction most likely extends to the regulation of mood and cognition in depression.29 Forexample, MDD is characterized by excessive negative thinking that is perceived as intrusiveand out of one’s control. Dysfunction of cortical inhibition may result in inadequate filteringof ruminative thoughts over time and thereby contribute to the onset or perpetuation ofMDD.29

2.7. Arterial Spin Labeling

ASL is a noninvasive procedure for quantifying CBF by measuring perfusion, in whicharterial blood is magnetically labeled as an endogenous perfusion tracer. ASL is based onthe subtraction of two consecutively acquired images. The first image is usually acquiredafter inversion of the arterial blood magnetization upstream of the region of interest (ROI).The second image is acquired without any manipulation of the arterial magnetization, andthe subtraction of both images provides information about the degree of perfusion. Whilemeasurements of perfusion are of direct diagnostic value in vascular disorders, perfusionmeasurements also serve as biomarkers for a broader range of physiological and pathophys-iological functions.

3.0. CHARACTERIZATION OF DISEASE STATE AND PROGRESSION 351

Published comparisons between ASL and PET in healthy volunteers demonstrate a closecorrelation both at rest30 and with task-related activation.31 Only a few studies have usedASL to study depression.32e35

ASL can be combined with any imaging sequence and theoretically provides a flow imagethat is completely independent of scanning parameters. ASL perfusion MRI can be used tolocalize task activation in a manner similar to BOLD fMRI.36 Indeed, ASL-based contrastderived from inversion recovery imaging of task activation was included in one of the earliestreports of fMRI in the human brain.12 ASL perfusion MRI can also be used as a measure ofbrain function at rest, independent of any sensorimotor or cognitive task, and can revealregional changes in brain function associated with development, behavioral states, or genetictraits.35 ASL measures a purely biological parameter, and may therefore be particularly valu-able for multicenter studies examining brain function on a variety of scanner platforms orlongitudinally.

2.8. Diffusion Tensor Imaging

DTI is a technique that quantifies the degree of diffusion (free or Brownian motion) of thewater molecules in the brain. This motion encounters different barriers in the body (cellmembranes, fibers, macromolecules, and proteins), which vary according to the location (intra-cellular or extracellular) and certain pathological modifications (abscess, intracellular edema,or tumors). Diffusion data provide indirect information about the structure surrounding thewater molecules. Myelinated fibers restrict the diffusion of water to the axis of the fiber bundle,resulting in visualization of white matter tracts. Beyond conventional MRI, DTI can provideadditional information on axonal integrity and bundle coherence, thus estimating the struc-tural efficiency of neural pathways.e.g.37 The metrics commonly used in DTI studies includefractional anisotropy (FA) andmean diffusivity (MD). High axonal integrity and resultant limi-tation of water diffusion in white matter is associated with high FAvalues and lowMD values,as in neurons with axons running parallel with concentric layers of the myelin sheath. LowestFA values are found during free diffusion where water molecules displace freely in all direc-tions.38 Using these coefficients, direction of a particular diffusion can be calculated, therebytracing the neuronal trajectory.

On the other hand, diffusion weighted (DW)-MRI aims at highlighting the differences inwater molecule mobility, irrespective of their direction of displacement. Apparent diffusioncoefficient (ADC), derived from DW-MRI is commonly used as an assessment of injury andaxonal integrity.37

3.0. CHARACTERIZATION OF DISEASE STATE AND PROGRESSION

3.1. Structural Changes

3.1.1. Volumetric Measurements

In early studies, neuroanatomical abnormalities using T1 images were measured usingstandard ROI methods, requiring investigators manually to identify a priori ROIs to quantifya volume of interest for group comparisons. More recently, voxel-based morphometry


(VBM), a whole brain semiautomatic technique, has been developed. VBM is used to performvoxel-wise comparison of the local concentration of gray matter between groups.39 This tech-nique overcomes the important drawback of regional bias of standard ROI methods. Resultsfrom studies using both methods are described below.

3.1.1.1. TEMPORAL LOBES

Studies of total temporal volume changes in MDD have produced inconsistent results.One study reported smaller left temporal volumes in MDD patients,40 but no other studiesreported any significant changes in total temporal volume (collapsed across hemispheres)and/or any laterality effect in unipolar MDD compared with healthy controls.41e45 However,the patient sample studied in a later study by Vythilingam and colleagues had the longestillness duration compared to the other studies.40 In this regard, it is possible that left-lateral-ized temporal lobe changes may reflect either progression of the disorder over time ora distinct pathophysiological process that affects risk or relapse.46

3.1.1.2. HIPPOCAMPUS

The hippocampus is the most extensively studied region in MDD, and the resultingfindings, albeit not homogeneous, seem to suggest that hippocampal volume reductionsare associated with MDD.46 While reduced hippocampal volume differences have beenthe most frequent finding,41e44,47e53 some groups have reported no difference betweenpatients and controls40,45,54e58 and tendencies toward volumetric enlargements40,47,59

have also been reported. Many studies have reported smaller hippocampal volumesin patients suffering multiple depressive episodes rather than in patients in remissionor experiencing their first episode.42,43,48,50,51,60 This could suggest that volumetricreduction of the hippocampus may be associated with repeated depressive episodes.48,50

However, the extent of volume reduction in the hippocampus has been shown not to beinfluenced by the severity and/or length of illness.42,50,59

Using VBM analysis, two studies reported decreased gray matter in the hippocampus,61,62

although two other studies reported no differences.63,64

3.1.1.3. AMYGDALA

It has been reported that amygdala sizemayalsovary in relation to illnessduration,while ageat onset of illness does not seem to have a major effect.49,65e68 Indeed, while unipolar patientsearlier in the course of illness tend to have increased amygdala volume,49,65e67 depressedpatients with a longer illness duration and a greater number of MDD episodes tend to showvolumetric reductions.41,42,54,55 This effect is specifically observed in female patients.46

In contrast, a meta-analysis of 23 VBM studies reported decreased gray matter volume inthe amygdala in first-episode patients compared with chronic patients and controls.69

3.1.1.4. FRONTAL LOBES

There are consistent reports of a volumetric reduction of the entire frontal lobe and/or theorbitofrontal cortex (OFC) in more severe MDD patients,44,48,55,70,71 but not in less severely illpatients.41,54,71 Interestingly, Lacerda and colleagues71 reported an inverse correlationbetween age and left lateral OFC volume in unipolar patients but not in healthy controls, sug-gesting that MDD duration may progressively affect the volume of the left lateral OFC. Other


studies have reported nonsignificant correlations between clinical variables and the volumesof frontal structures.41,54,55,70,71 However, studies using VBM methods have reported graymatter reductions in the OFC72,73 in medication-free MDD patients.

3.1.1.5. ANTERIOR CINGULATE CORTEX

Several volumetric studies have investigated whether depression may be related to alter-ations in the anterior cingulate cortex (ACC), particularly the subgenual cingulate cortex(sgACC), but have reported contradictory findings. This may be due to both the differentclinical and demographic features of the patient samples and the different methods usedto classify ACC subregions.46

No volumetric sgACC alterations have been found in less severely depressed remittedpatients,74,75 an exception being a study byMonkul and coworkers.55 In contrast, a decreasedvolume of the cingulate gyrus (excluding the subgenual area) has been found in currently illpatients, compared with remitted patients and healthy controls,76 although this change didnot appear to correlate with any clinical variable.

In contrast, graymatter reduction in the rostral cingulate cortex in patients withMDD rela-tive to healthy controls has been reported in a number of studies63,64,77 and longer illnessduration has been associated with greater gray matter reduction.69 Gray matter reductionin the OFC and sgACC was reported to correlate with recent stressful life events in controls,suggesting that increasing cumulative exposure to adverse life events is associated withsmaller gray matter volume in key prefrontal and limbic regions involved in stress, emotion,reward regulation, and impulse control.78

3.1.1.6. BASAL GANGLIA

Studies using an ROI approach have generally failed to detect changes in basal gangliavolume.41,44,79,80 Volumetric studies have reported inconsistent results, with some studiesreporting smaller caudate volumes in depressed patients and others reporting nodifferences.81

However, reductions in gray matter in the caudate and putamen were reported69 inpatients with treatment-resistant depression compared to recovered patients and controls.44

These studies suggest that the caudate nucleus and putamenmay be impaired inmore severesubtypes of depression.

3.1.1.7. THALAMUS

Gray matter reductions have been reported in the thalamus.77,82

3.1.1.8. SUMMARY OF VOLUMETRIC RESULTS

A family history of mood disorder has been hypothesized to play a critical role involumetric changes of the ACC, particularly the sgACC,83 although the structural find-ings of familial unipolar patients are contradictory.54,74,75,83 There are considerable vari-ations in terms of the demographic characteristics of patients, the imaging protocolsused, and analysis and clinical factors in the published studies, which could explainthe variability in findings. However, in summary, significant volumetric alterationshave been reported in the amygdala, basal ganglia, hippocampus, OFC, sgACC, and thal-amus in MDD.


3.1.2. White Matter Abnormalities

It has been hypothesized that microstructural changes in the white matter of frontal-subcortical circuits leads to a disconnection syndrome between frontal and subcorticalregions.84e86 Abnormalities in the white matter of subjects with affective disorders areusually measured using sMRI (white matter hyperintensities) in elderly patients and DTIin younger populations. White matter hyperintensities have been reported in older MDDpatients.87e90 White matter abnormalities have been associated with poor treatmentoutcomes,91 physical disability,92 and cognitive impairment.89,93,94

A number of studies have reported lower FAvalues in the medial frontal gyrus,84,95,96 pari-etal and occipitotemporal gyrus,95 inferior parietal portion of the superior longitudinalfasciculus,97,98 anterior limb of the internal capsule,98,99 uncinate fasciculus,100 cingulategyri,96,99e101 dorsolateral prefrontal cortex (DLPFC),101,102 right hippocampal gyrus,99 andleft striatum.103

Studies of family history report contradictory results. One study reported increased FAvalues in the splenium of the cingulate cortex,104 whereas another study reported decreasedFA values in the same region105 in first-degree relatives of MDD patients.

Within the DLPFC circuit, the anterior thalamic radiation connects the PFC to the thalamusthrough the anterior limb of the internal capsule. The uncinate fasciculus provides connec-tions between the frontal and temporal lobes. The findings summarized above providesupport for the theory that white matter abnormalities may play a role in a disconnectionsyndrome between frontal and subcortical regions and may contribute as a risk factor foraffective disorders.

3.2. Functional Changes

3.2.1. Depressed Mood and Negative Bias

The role of negative biases in information processing in the etiology and maintenance ofdepressive disorders has long been hypothesized.106 Early theories suggested that thesebiases affect all aspects of information processing, with depressed patients showingenhanced attention, interpretation, and memory for all negative emotional material.106

More recent evidence indicates that cognitive processes are not uniformly biased in depres-sion and that the distinctions between implicit and explicit aspects of performance, atten-tional engagement and disengagement, and perceptual and conceptual levels of processingare relevant.107

The lack of consistent evidence for biased attentional processing in depression has ledsome researchers to hypothesize that depression is characterized by memory but not atten-tional bias, whereas anxiety is characterized by attentional but not memory bias.108e110 Ithas also been proposed that there is little evidence for subliminal attentional bias in depres-sion, and that an attentional bias in depression is typically only found when the material isself-referent and is presented for long (> 1000ms) durations, which may reflect difficulty indisengaging attention from negative emotional information.109,111 Measures of facial expres-sion recognition have typically revealed a bias toward labeling ambiguous facial expressionsas negative and/or the perception of positive cues of happiness being reduced in patientswith depression.112 However, there is evidence to support consistently enhanced selective


memory for negative material particularly seen in explicit memory paradigms.113,114 Forexample, if patients with MDD are asked to recall positive and negative self-descriptorsencoded in a classification task, they show a tendency to remember negative rather than posi-tive words.

fMRI studies provide converging evidence for the role of limbic circuitry in negative affectiveprocessing biases inMDD.115 Thus, for example, in implicit face processing paradigms, depres-sion is associated with exaggerated responses in the amygdala, ventral striatum, and insula tonegative (sad or fearful) expressions of emotion,116e120 whereas responses to happy facialexpressions in the amygdala, hippocampus, putamen, and thalamus appear to be reduc-ed.121e123 Although these subcortical areas are usually regarded as important in the initial eval-uation of emotion, some of the observed effects may underpin attentional bias. The visualmechanisms for increasing attention to salient and important stimuli are thought to be modu-lated by signals from both amygdala and frontoparietal circuitry.124 Siegle and colleagues125

found that amygdala responses to negative words were no longer visible after 10 s in healthycontrolsbutpersisted indepressedpatients for ameanof25 s. Increasedactivityof the amygdalais also seen in conjunctionwith the expectation of a negative stimulus.MedicatedMDDpatientscued to anticipate the arrival of disgusting pictures displayed greater BOLD activation in someregions, including the dorsal amygdala and sublenticular nucleus, compared with healthysubjects.126 In contrast, few studies have reported negative results. One study reported thata group of medicated MDD subjects were found not to differ from healthy control subjectswhen presented with sad or fearful faces.122

Alternatively, it has been suggested that the negative bias observed in depression reflectsimpaired top-down cognitive control127,128 linked to reduced activity in cortical regions,including anterior cingulate cortex, DLPFC, and rostral ACC (rACC).129e132 It has beenproposed that such reduced activity of a top-down system allows unrestrained activationin emotional regions of the brain. Hence, the subcortical regions, unchecked by cognitivecontrol, are thought to reinforce cognitive biases, leading to increased awareness of negativestimuli, which in turn perpetuates depression.133 In neuroimaging studies, depressedpatients show consistent amygdala hyperactivity in response to negative emotionalstimuli,125 often combined with reduced responses in areas such as the DLPFC involved inthe effortful regulation of affective states.120,134,135 A similar pattern has been reported inCBF studies using PET.136 In contrast, Dichter and colleagues observed increased DLPFCactivity when attending to sad faces.137 Similar results were reported during an emotion-interference task: depressed patients showed hyperactivity in the amygdala, DLPFC, anddorsal ACC when attending to happy faces.138 Dichter and colleagues proposed that rela-tively greater prefrontal brain activation was required to disengage from the sad images torespond to the target events.137

In contrast, reduced amygdala activation in response to positive stimuli has been demon-strated in a small number of studies.122,139 Increased DLPFC activity to positive versus nega-tive words in both a Stroop and an emotional categorization task was observed in dysphoricparticipants relative to controls.120 Reciprocal connections between the prefrontal cortex andlimbic structures when processing negative and positive stimuli may underlie the hyposen-sitivity observed in the amygdala to positive stimuli. Thus, increased control exerted bycortical regions on the response of limbic structures to positive stimuli might result in anhe-donia, a core symptom of depression. On the other hand, decreased control exerted by


cortical regions on the response of limbic structures to negative stimuli may be a cause of thenegative bias observed in depression.

Hence, coordinated responses to affective stimuli may provide a neural assay of emotionalbias or the salience level of affective stimuli, and help us to understand the neural mecha-nisms underlying behavioral biases. Such biases may be driven by enhanced negative eval-uation within limbic areas coupled with deficient higher-order emotional modulation ofcognitive processes within areas such as the prefrontal cortex.140

There is growing evidence that such biases may be present outside episodes of majordepression and could represent trait vulnerability markers. For example, there have beenreports of increased negative versus positive emotional processing in healthy volunteersat a high risk of developing depression141e143 or with a history of major depression.144

Although some biases appear to be resolved or absent in high-risk volunteers outsidea depressive episode,145 they can be triggered following an induction of negativemood.146 Thus, rather than being a simple symptom of depression, processing biasesmay be latent vulnerability mechanisms that can be readily triggered or exaggerated bydecreases in mood or lowered serotonin function.

3.2.2. Anhedonia and Hypersensitivity to Negative Feedback

MDD has been associated with a hyposensitive or blunted response to reward (anhe-donia) and hypersensitivity to punishment.147

3.2.2.1. HYPERSENSITIVITY TO PUNISHMENT

The hypothesis predicted by models of learned helplessness,148 i.e. that patients withMDD manifest an abnormal response to negative feedback, is consistent with findingsthat depressed patients respond catastrophically to error feedback on memory or plan-ning tasks. Elliott and colleagues demonstrated that a depressed group was not simplyworse at planning than controls, regardless of difficulty, as both groups solved thesame number of problems. However, if MDD patients made an error on a trial, theirperformance deteriorated rapidly, which was termed a catastrophic response to perceivedfailure. This deficit was shown to correlate with severity of depression149 and to be specificto depression.150 It has been shown that similar deficits are also evident in remitteddepressed patients,151 suggesting that abnormal reactions to negative feedback mayextend to individuals with increased risk of depression, even in the absence of symptoms.A catastrophic response to negative feedback may be due to perceived failure triggeringfurther failure-related thoughts, thereby interfering with subsequent performance.106

Thus, patients with MDD could be hypersensitive to punishment. Alternatively,depressed patients may be hyposensitive to punishment by failing to use negative feed-back to improve performance.150,152 Holmes and Pizzagalli153 found that participantswith high scores on the Beck Depression Inventory were significantly less likely to adjusttheir responses after errors than participants with low scores on the inventory. Sucha failure in posterror performance adjustment could reflect underlying deficits in motiva-tion or performance monitoring, or a generally blunted response to reinforcement ratherthan hypersensitivity to punishment.

Murphy and colleagues154 found that MDD patients performed as well as controls afteraccurate negative feedback, but were more sensitive to misleading negative feedback. This


may be interpreted as a tendency to exaggerate the importance of uncertain or misleadinginformation that could lead to a perceived lack of control.155 In turn, this could bias futureactions and cause a cycle of learned helplessness.148 In summary, depression seems to be char-acterized by maladaptive responses to negative feedback by various mechanisms, includingfailure to adapt, reduced sensitivity to punishment, and/or learned helplessness.

3.2.2.2. HYPOSENSITIVITY TO REWARD

Anhedonia, the inability to experience pleasure, is one of the core symptoms of depres-sion.147 Willner156 postulated that a functional impairment of the mesolimbic dopamine(DA) pathway underlies the MDD symptoms of anhedonia and loss of motivation.This hypothesis is consistent with findings showing that euphoria is correlated withamphetamine-induced DA release in the human ventral striatum157 and that CBF differ-ences between depressed patients and controls have been identified in regions innervatedby the mesolimbic DA pathway, including the ACC, amygdala, striatum, and prefrontalcortex.158,159

Using a dopaminergic probe consisting of the oral administration of d-amphetamine Trem-blay and colleagues160 showed that the severity of depression was highly correlated with therewarding effects of d-amphetamine in a group of unmedicated depressed patients, and thatMDD subjects with severe symptoms reported significantly greater rewarding effects thancontrols. These results provide evidence for hypersensitivity of the brain reward system inMDD that could be related to a DA hypofunction.

McFarland and Klein161 reported that currently depressed subjects, but not remitteddepressed subjects, have a diminished responsiveness to anticipated reward but not to antic-ipated punishment. An fMRI study investigating the neural responses to monetary incen-tives reported that unmedicated MDD patients and controls did not differ in theirbehavioral responses or in nucleus accumbens activation.162 However, MDD patientsshowed increased activity of the ACC in anticipation of increasing monetary gains, whereasthe ACC was activated in anticipation of increasing losses in controls. Knutson andcolleagues162 interpret these results as supporting the presence of increased conflict duringanticipation of gains and a reduced ability to discriminate gain from nongain outcomes inMDD patients. Similarly, Forbes and colleagues163 reported reduced striatal activation indepressed adolescents during reward anticipation and outcome. In addition, using a mone-tary incentive delay task, Pizzagalli and coworkers164 reported reduced putamen activationduring reward anticipation and reduced nucleus accumbens and caudate activation duringreceipt of reward in unmedicated MDD patients.

Smoksi and colleagues165 investigated whether patients with MDD demonstrated hypo-responsivity in striatal brain regions and/or hyperresponsivity in cortical brain regionsinvolved in conflict monitoring using a Wheel of Fortune task designed to probe responsesduring reward selection, reward anticipation, and reward feedback. The MDD group wascharacterized by reduced activation of striatal regions during reward selection, anticipa-tion, and feedback; by hyperresponsivity in OFC during reward selection; and by decreasedactivation of the middle frontal gyrus and the ACC during reward selection andanticipation.

Epstein and colleagues166 observed decreased activity in the ventral striatum indepressed patients in response to positive stimuli compared with controls. Similarly,


Surguladze and colleagues119 found a linear response to expressions of increasing happi-ness in the right putamen in healthy controls but not in depressed patients. However,a linear response to expressions of increasing sadness in the left putamen was observedin depressed patients.

It is well established that DA neurons code a specific phasic (short duration) reward-learning signal, described by temporal difference theory. A study by Kumar andcolleagues167 examined whether patients with MDD have blunted temporal differencereward-learning signals and if the extent of alteration in temporal difference signals in majordepression correlates with illness severity ratings. Their results showed that long-term-medicated MDD patients exhibit a reduced reaction to reward-learning signals in the ventralstriatum and ACC and the magnitude of the abnormal signals in MDD correlates with illnessseverity ratings.

Preliminary results from an fMRI study of appetitive conditioning showed that dysfunc-tional learning in both appetitive and aversive learning conditions is associatedwith a patternof dysfunction in the ACC, amygdala, lateral OFC, and striatum in unmedicated MDDpatients.168

Finally, a study of participants who had recovered from MDD, and therefore were nolonger influenced by mood state or current medication usage, revealed reduced activationto pleasant taste and picture stimuli in reward areas such as ventral striatum compared tohealthy controls.169 These findings indicate that blunted ventral striatal responses duringreward are state-independent and may represent a potential endophenotype of MDD.

3.2.3. Impaired Learning and Memory

In addition to negative bias in attention and memory, patients with MDD are reported tohave impaired working memory.170 Some authors suggest that working memory impair-ments in MDD are due to persistent deficits in selective attention.171 In contrast, deficits inlong-term storage and retrieval of declarative memory in MDD have been reported to beinfluenced by the number of depressive episodes, hippocampal volume reduction, hypercor-tisolemia, and stress,50,172 suggesting that these symptoms are a consequence rather than anetiological factor in depression.170 Rose and colleagues173 showed that cognitive loadincreased rACC activity in MDD using an n-back working memory task. This hyperactivitywas proposed to be a possible trait marker as it has been reported to persist after clinicalrecovery.174

3.2.4. Impaired Executive Function

Impairments in executive function in depressed subjects refer to abnormalities in cogni-tive behaviors that control and integrate neural activities, including selection strategies,planning, and monitoring performance. These impairments are not specific to MDD andusually recover to normal levels during remission. However, response speed has beenfound to be unrelated to concurrent depressive symptoms and to remain impaired in recov-ered depressed patients who are off medication175 (state independence). Specifically,inspection time, a measure of the speed of information processing that does notrequire a speeded motor response, has been found to be slower in subjects with unipolarmajor depression than in age-, IQ-, and sex-matched controls, independent of currentmood.176


3.2.5. Impaired Social Cognition

Social cognition refers to the ability to interpret and predict the behavior of others in termsof their beliefs and intentions, and to interact in complex social environments.iii

Social cognition encompasses facial perception, emotional information processing(including both perception of emotional information in the environment and regulation ofmood), theory of mind (understanding others’ beliefs and intentions), self-reference, andworking memory.177 Brain regions that are involved in social cognition include the ACCcingulate, amygdala, fusiform gyrus, OFC, and PFC.177 These same brain regions arereported to be functionally and/or structurally abnormal in MDD patients.178 A significantclinical feature of MDD is often a profound impairment in social functioning. Patientshave been reported to exhibit reduced ‘social competence’,179 fewer social interactions,180

reduced awareness of others’ emotions,181 and to have reduced reward value associatedwith social interaction.182 These negative interpersonal experiences appear to causedepressed individuals to isolate themselves, thus perhaps perpetuating their depressivestate.183

3.2.5.1. FACIAL EMOTION PROCESSING

Given their ubiquitous nature, the ability to recognize facial expressions is crucial for intactinterpersonal functioning.184 Studies that have examined facial emotion processing in acutelydepressed patients have reported a generalized emotion recognition deficit185e194 andimpaired recognition of happy facial expressions, relative to matched controls.190,192,195e200

Enhanced recognition of sad facial expressions has also been consistently reported in acutelydepressed patients.201e204 Other studies have reported evidence of a negative bias duringfacial expression recognition and detection tasks,200,205e211 including a tendency to identifyneutral faces as sad in patients with moderate to severe depressive symptoms, comparedwith healthy controls.212,213 This bias is accompanied by selective attention to negativelyvalenced faces depicting sadness122,146,195,211 and anger.214 Overall, these studies point towarda processing bias involving enhanced attention to and recognition of negatively valencedfaces during active states of depression that may be accompanied by a tendency to mislabelpositively valenced faces as sad and to misjudge (i.e. amplify) the degree of negative emotionconveyed in facial expressions.

Evidence from fMRI studies suggests that patients with acute MDD demonstrateincreased activation in the amygdala, OFCs, and ventral striatum to masked118,215,216 andunmasked117,119,217e220 displays of negatively valenced faces (e.g. expressions of disgust,fear, or sadness). However, conflicting findings exist,119,219 which may stem from the useof different emotional processing paradigms and from differences in the clinical status ofpatients in terms of comorbidity, depression severity, illness burden, and medication.

The functional connectivity between prefrontal and subcortical regions in patients withMDD has been examined. Specifically, during negative facial processing tests (implicit andexplicit) consisting of angry and sad facial expressions, the dorsal anterior cingulate and

iiiFor further discussion of impaired social cognition in psychiatric disorders, please refer to Westphal et al. in

Chapter 8, Functional Magnetic Resonance Imaging as a Biomarker for the Diagnosis, Progression, and

Treatment of Autistic Spectrum Disorders, in this volume.


the precuneus, a region implicated in self-related mental representations, have been shown tohave reduced connectivity with the OFC in unmedicated patients withMDD.221,222 Decreasedconnectivity between the dorsal anterior cingulate and OFCmay contribute to dysfunction inthe cognitive control of emotional processing. In addition, decreased connectivity betweenthe precuneus and the OFC may contribute to the disturbances in self-referential processesthat occur in MDD patients.221 Further, functional connectivity between the OFC and theDLPFC was increased in patients compared with controls during negative facial processingand this may give rise to the negative processing bias inherent in the disorder.222 Similarly,it has been reported that a chronic and recurrent course of illness is associated with reducedfunctional connectivity between the amygdala and DLPFC while passively viewing angryand sad faces and is associated with illness severity, indicating that MDD patients withreduced connectivity between these regions have a more pervasive and severe course ofillness.223 In addition, disruptions in functional coupling between the amygdala and subge-nual cingulate, a region also implicated in assessing the salience of emotion and regulation ofemotions, have been reported during facial processing tasks.218,224

Studies have also examined the relationship between patterns of neural activation inresponse to emotional facial expressions and mood state. For example, depression severityhas been shown to negatively correlate with the extent of activation in the fusiformgyrus,119,121 ACC,225 and amygdala.139 Similarly, subgenual cingulate and visual corticalresponses to sad but not happy facial stimuli correlated with changes in symptoms duringantidepressant therapy.226 However, a significant number of other studies failed to finda significant association between the level of depression and neural activity in response tofacial emotions.72,118,215,216,227,228 It is possible that limited sample sizes and the inclusionof patients with varying levels of depression may contribute to these contradictory findings.

3.2.5.2. THEORY OF MIND

Theoretical models propose that the theory of mind draws on both cognitive (e.g. under-standing another’s perspective) and affective (e.g. an emotional response to the feelings ofothers) processing resources.229

Neuroimaging and behavioral studies of theory of mind implicate a core network ofneural regions that include cognitive (e.g. DLPFC), affective (e.g. mPFC and anterior para-cingulate cortex), and memory systems (e.g. posterior cingulate and temporal poles). More-over, neuroimaging evidence also implicates the posterior superior temporal sulcus, whichis involved in biological motion perception including socially relevant directional cuessuch as the eye gaze of others, and the adjacent temporoparietal junction, which is involvedin the attribution of beliefs to others and is thought to be critical for theory of mindability.221

Research into impaired theory of mind in patients with mood disorders is starting to gainattention after findings that impaired theory of mind ability may be associated with a poorclinical and functional outcome in these patients.221 A small number of studies conductedin actively depressed patients suggest that patients show impairments on theory of mindtasks that involve decoding mental states from available information, such as facial expres-sions, tone of voice, gestures, and reasoning183,230 (but for contradictory findings, see 231), andtasks that involve reasoning about mental states by combining contextual information andprior knowledge of an individual or situation to understand behavior.232


To date, studies examining the neural correlates of theory of mind processing in patientswith mood disorders have been confined to investigations of patients with bipolardisorder.221 As brain regions involved in theory of mind are reported to be structurallyand/or functionally abnormal in depression, it appears likely that impairments in theoryof mind ability may be apparent in MDD patients.

3.3. Resting State Abnormalities

‘What does the brain do, when not engaging in a task and what does the brain do at“rest”?233 These are two of the questions that have intrigued neuroscientists since MarcusRaichle first coined the term default mode in relation to resting state brain function.234

The concept of a default mode network arises from an emerging body of evidence demon-strating a consistent pattern of deactivation across a network of brain regions, including theprecuneus/posterior cingulate, medial PFC, and medial, lateral, and inferior parietal cortex,that occurs during the initiation of task-related activity.234 Although deactivated during taskperformance, this network is active in the resting brain with a high degree of functionalconnectivity between regions. This network was termed the default mode of brain activityto denote a state in which an individual is awake and alert, but not actively involved in anattention-demanding goal-oriented task. The more demanding the task, the stronger is thedeactivation of the default mode network.235,236 Interestingly, brain energy utilization hasbeen shown to be only slightly greater in the active than the resting brain.237,238

The issue of understanding how different brain regions are connected functionally at restand during a task has become a vital question in neuroscience. Different neuroimagingmodalities (EEG, fMRI, and PET) can be used to assess neural activity at rest and to comparehealthy individuals and patients with MDD.

3.3.1. fMRI

The resting state of the brain has been widely investigated using fMRI.235,239,240 Func-tional connectivity refers to the temporal correlation between fluctuations in the BOLDsignal of discrete anatomical regions.241 More generally, functional connectivity betweentwo brain regions is considered in terms of the temporal coherence or correlation betweenthe oscillatory firing rates of neuronal assemblies.242 Assessment of functional connectivitycan be achieved through a number of methods, two of which, the ROI seed-based correlationapproach and independent component analysis (ICA), are most commonly used. The ROIapproach uses regression or correlation analyses to examine temporal coherence betweena selected voxel and the time-series of all other voxels in the brain.243 Unlike seed-basedROI approaches, ICA is a model-free approach and is not bounded by a priori predictions.ICA decomposes data into maximally independent components (temporal or spatial), rep-resenting the characteristic time and spatial signatures of the sources underlying therecorded mixed signals.244

Anand and colleagues245 investigated differences in corticolimbic activity and connec-tivity between depressed patients and healthy controls. Depressed patients had increasedactivation of cortical and limbic regions. Decreased connectivity was observed between therACC and amygdala, the rACC and dorsomedial thalamus, and between the rACC, precu-neus, and caudate in depressed patients compared to healthy subjects. A further study


reported that the DLPFC was decoupled from the hippocampus, rACC, and sgACC, whichmay indicate reduced connectivity.246 Interestingly, connectivity between the rACC andsgACC was reported to increase in response to deep brain stimulation.240 In another study,the connectivity patterns of three seed regions, the DLPFC, precuneus, and rACC, werereported to converge in the region including the sgACC with some extension into an areaof dorsomedial prefrontal cortex (DMPFC). The authors described this region as the ‘dorsalnexus’ and reported increased connectivity between the dorsal nexus and the rostral andposterior cingulate, and ventral medial and dorsolateral PFC in MDD patients comparedwith controls.247 Increased connectivity was also reported between the DLPFC, medialOFC, and rACC,248 and between the rACC and thalamus.249 Increased connectivity betweenthe hippocampus and the rACC leading to the mPFC was interpreted as increased excitationwithin limbic/paralimbic regions, whereas decreased connectivity to and from the DLPFCwas interpreted as increased neural inhibition in the lateral PFC.250

Increased resting state connectivity between the rACC and left anterior insula was foundto be predicted by the concentration of glutamate in rACC.249 Greicius and colleaguesreported that the subgenual cingulate disproportionately contributed to the connectivity ofthe default mode network in MDD patients, with increases in connectivity associated withdepression refractoriness, or the duration of the current depressive episode.240 There wasalso increased connectivity in the thalamus during rest. It was proposed that increasedconnectivity in affective regions may detrimentally affect connectivity in regions associatedwith cognitive processing such as the dorsal ACC.240


Both currently depressed patients and patients with lifelong depression were reported tohave decreased frontal activity and increased frontal alpha power, measured by quantitativeEEG.251e253 This suggests that frontal asymmetry is an endophenotype for depression. It hasalso been reported that increased cognitive vulnerability to depression was associated witha reduction in left frontal activity. After 3 years, both cognitive vulnerability and frontalasymmetry predicted the onset of the first episode of depression.254

The hypothesis of a default asymmetric mode of depressed patients is based mainly uponthe finding of a relative decrease in neural activity. One possible way to investigate this hypo-activation in the left frontal cortex is to measure the correlation between signals of brainactivity collected from different cortical regions255 using partial directed coherence (PDC)analysis.256 This method is of particular interest because of its ability to distinguish directand indirect causal influences regardless of any common extraneous influences or sources.257

PDC analysis therefore offers an opportunity to analyze quantitatively and compare the func-tional connectivity in the brain of depressed patients. Using this approach, Sun andcolleagues255 have reported that depression is characterized by a hemispheric asymmetrysyndrome.

3.3.3. Perfusion Arterial Spin Labeling

Few studies have investigated perfusion abnormalities in depression using ASL. Onestudy reported significant hyperperfusion in the subgenual cingulate in chronic and treat-ment-resistant MDD patients.35 In addition, Clark and colleagues33 reported that an increasein baseline perfusion in the sgACC predicted treatment response to partial sleep deprivation


and was reduced after treatment. In addition, a study on late-life depression reported anincrease in normalized white matter CBF.258

3.3.4. PET

Hypermetabolism has been reported in the sgACC in MDD and this was shown to corre-late with illness severity.259 However, there is some evidence for the reverse relationship.83

Using FDG-PET, Suwa and colleagues reported that, in patients with drug treatment-resistantdepression and bipolar disorder, hypometabolism in the superior frontal gyrus and hyperme-tabolism in the inferior temporal gyri, compared to controls, predicted response to electrocon-vulsive therapy (ECT).260

3.3.5. Receptor Binding

3.3.5.1. SEROTONIN 5-HT1A RECEPTOR SIGNALING ABNORMALITIES IN MAJOR

DEPRESSIVE DISORDER

Decreased 5-HT1A receptor binding has been consistently reported in multiple brain areasof patients with MDD.261,262 The 5-HT1A receptor is a G protein-coupled receptor concen-trated in regions that receive serotonergic input from the raphe nuclei such as the frontalcortex, amygdala, hippocampus, and hypothalamus.263,264 The 5-HT1A receptor servespredominantly as an autoreceptor controlling serotonin release and synthesis in the raphenuclei, thus reducing serotonergic transmission to its projection areas,265 and as a postsyn-aptic receptor in the frontal and limbic projection regions.266

PET data are largely suggestive of reduced 5-HT1A receptor binding in MDD. reviewed in 267

In a 11C-WAY-100635 (a selective 5-HT1A receptor antagonist ligand) PET study, reduced5-HT1A receptor binding in the medial temporal cortex, hippocampus, and midbrainraphe was found in depressed bipolar and MDD patients with familial forms ofillness,261 and in unmedicated recurrent depressed patients compared with healthycontrols.268 In an independent study using 11C-WAY-100635, Sargent and colleagues262

reported a widespread reduction (frontal, temporal, and limbic cortices) in 5-HT1A

receptor binding in both medicated and unmedicated individuals with MDD. In contrast,Bhagwagar and colleagues reported decreased receptor binding in cortical regions, butnot in the raphe nuclei, in recovered depressed males.269 Hirvonen and colleagues270

replicated this finding in drug-naive individuals with MDD. Reduced 5-HT1A receptorbinding in the dorsal raphe nucleus of elderly depressed subjects271 and in the sgACC,pgACC, and lateral orbital and mesial temporal cortices of postpartum MDD subjects228

has also been reported. Animal and postmortem studies are consistent with the humanPET literature.85 Thus, it has been proposed that reduced 5-HT1A receptor bindingmight represent trait vulnerability for depression. However, the lack of effect of selectiveserotonin reuptake inhibitor (SSRI) treatment and hydrocortisone challenge on 5-HT1A

receptors in recovered patients with MDD suggests state independence of thisabnormality.269,272

It should also be noted that the 5-HT1A PET literature is not entirely consistent, and Parseyand colleagues273 reported that 5-HT1A receptor binding was increased across all regions inantidepressant-naive MDD patients. Therefore, it appears that the choice of reference regionand outcome measure can produce different 5-HT1A receptor binding results in MDD, andthis issue requires further work to be resolved.


3.3.5.2. CHANGES IN 5-HTT BINDING

The 5-HT transporter (5-HTT) contributes to the regulation of serotonergic neurotransmis-sion through the reuptake of 5-HT in the synaptic cleft. An inverse relationship existsbetween 5-HTT binding and extracellular 5-HT levels. A study using the 5-HTT radioligand11C-(þ)-McN5652 reported a 23% increase in thalamic 5-HTT binding in medication-freeMDD subjects compared with controls.274 In contrast, Parsey and colleagues275 reporteddecreased 5-HTT binding in the amygdala and midbrain but no change in other regions ofthe brain using the same radioligand. It was later reported that lower 5-HTT binding inthe ACC, amygdala, and midbrain predicted the absence of remission at 1 year.276 Similarly,Reimold and colleagues277 reported reduced 5-HTT binding in the thalami (but not otherregions such as the amygdala and midbrain) of patients with MDD, and a negative correla-tion between 5-HTT availability in the amygdala and thalamus and depression and anxietyscores. In contrast, although no overall intergroup difference in 5-HTT binding was detected,scores on the Dysfunctional Attitude Scale were found to positively correlate with increased5-HTT binding in the anterior cingulate, putamen, and thalamus.278 This finding is consistentwith the data of Cannon and colleagues,279 who showed that depressed, unmedicated MDDpatients had increased 5-HTT binding in the thalamus (24% increase), periaqueductal graymatter (PAG; 22%), insula (15%), and striatum (12%) relative to healthy subjects. Further-more, the depression-associated personality trait, neuroticism, is reportedly associatedwith higher thalamic 5-HTT binding,280 and clinically depressed patients with Parkinson’sdisease also show increased 5-HTT binding in the PFC compared with healthy controls.281

3.3.5.3. DOPAMINE

Cannon and colleagues282 reported that D1 dopamine receptor binding was reduced in thecaudate of depressed patients and that this difference correlated with disease duration andanhedonia rating. This difference was more evident in the NAc and putamen, regions thatplay a role in reinforcement learning, which can be profoundly affected in MDD. Similarly,Dougherty and colleagues283 reported that D1 receptor hypofunction in the striatum distin-guished depressed patients from controls. There are inconsistencies in the literature for D2

receptors, with PET studies showing higher,284,285 lower,286 or unchanged287,288 striatal D2

receptor density in MDD compared with controls.270

3.4. Biochemical Alterations in Major Depressive Disorder Changes DetectedThrough 1H-MRS


NAA levels in the caudate,289 PFC,290 and ACC291 were reported to be reduced in MDDpatients, compared with healthy controls. Portella and colleagues292 reported that levels ofNAA in the ventromedial prefrontal cortex (VMPFC) were reduced only in patients withchronic and recurrent depression and that normal levels were seen in treatment-naivepatients. It has been proposed that NAA levels correlate with the age of onset of MDD292

and the severity and duration of illness.293,294 Treatment-resistant patients had decreasedNAA levels in the thalamus295 and ACC,291 and normal levels in amygdala,296 hippo-campus,24 and basal ganglia.297 In contrast, no significant differences in NAA levels between


patients with MDD and controls were reported in the basal ganglia,298,299 PFC,300 DLPFC,293

ACC,300,301 putamen,289 and thalamus.289 Ameta-analysis ofMRS studies reported thatMDDpatients had similar NAAvalues to those of controls in both the basal ganglia and frontal lobestructures.23

No significant differences in NAA levels in pediatric MDD patients were reported inthe DLPFC,76,302,303 caudate,304,305 putamen,304 ACC,306 occipital cortex (OCC),306 OFC,307

amygdala,308 and thalamus.304 Consistent with this, a meta-analysis reported no significantalteration in NAA levels in pediatric MDD patients.23

3.4.2. Choline Compounds

Higher values of Cho have been reported in the basal ganglia of MDD patients,289,298,299,309

although one study reported significantly lower values in the basal ganglia that increasedwithfluoxetine (Prozac) treatment.297 Another two studies reported that choline levels in the basalganglia decreasedwith successful treatment with fluoxetine.309,310 Ameta-analysis performedusing the results from these three studies showed no significant decrease in choline levels withantidepressant treatment in the basal ganglia.23 No significant alterations were found in theOCC,311 ACC,294,300,301 DLPFC,293 or the amygdala.296 Treatment-naive patients had increasedlevels of choline in the hippocampus that correlated with past burden of illness.312 However,chronic patients had increased levels in the VMPFC that correlated with duration of illness.292

Pediatric MDD studies have reported increased choline levels in the caudate,304,305

DLPFC,302 and OFC.307 One study reported no change in the DLPFC in pediatric patients76

and in another study reduced choline levels were reported in the amygdala in pediatricpatients.308 A meta-analysis performed over three studies indicated similar Cho values inthe frontal lobe structures of pediatric patients as in controls.23

3.4.3. Myo-Inositol

In cerebrospinal fluid (CSF), markedly reduced levels of myo-inositol have been reportedin depressed patients with unipolar or bipolar affective disorder.313 Under double-blindconditions, the intake of myo-inositol has been reported to lead to an improvement indepression.314

Reducedmyo-inositol levels in the PFC 290,300,314,315 and normal levels in the basal ganglia289

and ACC301 were reported in MDD patients. Treatment-naive patients showed an increase inmyo-inositol levels in the hippocampus,312 whereas recovered depressed patients showed anincrease in the ACC myo-inositol levels.316 One study reported that pediatric patients had anincrease in myo-inositol levels in the DLPFC.76 In contrast, Mirza and colleagues306 reportedno significant alterations in myo-inositol levels in the ACC in MDD patients.

3.4.4. GABA

Studies dating back to the early 1980s have demonstrated abnormally low levels of GABAin the CSF and plasma of depressed patients. More recent findings have augmented this bodyof evidence by demonstrating specific neurophysiological effects that are likely to be relatedto GABAergic changes in the brains of individuals suffering with MDD.317

Sanacora and colleagues318 reported that GABA levels in the occipital cortex (OCC) werereduced in MDD patients. This finding was later replicated in another large sample of MDDpatients.311 A similar pattern of results in the OCC was reported in recovered depressed


patients.319 This suggests that reduced GABAmay be a trait marker of susceptibility to affec-tive disorders as opposed to a biochemical marker of active illness.319 Occipital cortex andACC GABA levels were quantified in treatment-resistant patients and healthy controls,and it was observed that treatment-resistant patients had the lowest GABA levels in theOCC,320 which increased with successful ECT treatment.321 Similar results were reportedafter 2months of treatment with SSRI antidepressants.322

In addition, a reduction in GABA levels in the PFC was reported in MDD,323 whereas PFCGABA was increased with antidepressant treatment in cocaine-dependent subjects.324

Reductions in both occipital and prefrontal cortex GABAwere greatest in patients with treat-ment-resistant depression or melancholic major depression,311,320 suggesting that GABAergicabnormalities differ between MDD subgroups.

One study provided evidence for GABAergic deficits in MDD by showing a reduceddensity of GABAergic interneurons in various cortical regions of patients with MDD.325

Another study reported that the elevated resting state activity in various cortical and subcor-tical regions observed in MDD might be due to these GABA reductions. Both GABAA andGABAB receptors may be dysfunctional in MDD, as animal models have consistently showndecreased GABAA/B receptor expression and sensitivity in metabolically hyperactive corticaland subcortical structures.326

3.4.5. Glutamate

As glutamate is difficult to measure by MRS, the Glu:Gln ratio or combined Glu and Glnpeaks, termed Glx, has been measured and reported, particularly in early studies (see Section2.6.5). Glx levels were found to be decreased in MDD across various regions includingDMPFC,323 VMPFC,323 ACC,294,301 hippocampus,327 amygdala,296 and left DLPFC.293 More-over, Glx levels in the ACC, amygdala, and DLPFC normalized after successful ECT treatmentin treatment-resistant depression.293,294,296 In addition, reduced glutamate levels in the VMPFCand ACC were only observed in chronic and recurrent depression and correlated with illnessduration.291,292 In contrast,Milne and colleagues312 and Price and coworkers320 found nodiffer-ence in glutamate levels in thehippocampusand in theACCandOCC, respectively. In theACC,one study found a decrease in Glx levels but no change in the glutamate levels, except for inseverely depressed patients,301 thus suggesting a reduction in glutamine in MDD. Walter andcolleagues reported patients with increased anhedonia had reduced glutamine but normalglutamate levels.328 In the hippocampus, both Glx and glutamine signals were reduced311,327

and Sanacora and colleagues reported elevated glutamate levels in theOCC,with no abnormal-ities in glutamine.311 In remitted patients, Hasler and coworkers329 reported no significantabnormality in Glx levels in the DMPFC and VMPFC and Bhagwagar and coworkers319

reported increased Glx levels in the OCC compared to healthy controls. In addition, elevatedserum, plasma, and CSF levels of glutamate have been reported in MDD.330e333

4.0. CHARACTERIZATION OF THERAPEUTIC MANIPULATIONS

4.1. Pharmacological Studies

Many studies have investigated whether pharmacological or other therapies can reversethe impairments observed in MDD and thereby potentially identify biomarkers for treatment

4.0. CHARACTERIZATION OF THERAPEUTIC MANIPULATIONS 367

response. An increasing number of studies have examined the actions of antidepressants onthe responses of healthy controls during specific tasks and attempted to determine whetherthe observed effects can be translated to a clinical population.

4.1.1. Negative Bias

Using fMRI, Fales and colleagues134 demonstrated that MDD patients showed hypoactiv-ity in the right DLPFC and increased activation in the amygdala when performing cognitivetasks that required participants to ignore negatively valenced distracters. After 8 weeks ofSSRI antidepressant treatment, patients showed significantly increased DLPFC activity tounattended fear-related stimuli and no longer differed from controls in either DLPFC oramygdala activity during an emotional interference task.227 In addition, antidepressantshave been reported to reduce amygdala responsiveness to negative stimuli when presentedoutside conscious awareness.118 Harmer and colleagues have reported that both acute andchronic antidepressant treatment reverse negative biases in healthy controls, dysphoricparticipants, and patients with MDD.107,120

Similarly, using PET Mayberg and colleagues reported that following recovery fromdepression (after 6 weeks of treatment with the SSRI fluoxetine), the reversal patterninvolving the same regions was observed, with limbic metabolic decreases and neocorticalincreases. A significant inverse correlation between subgenual cingulate and right dorsolat-eral prefrontal activity was also demonstrated in both conditions.136 Resting hypoactivationin DLPFC has long been a recognized concomitant of depression, and this resting hypoactiv-ity has been observed to increase toward normal levels with antidepressant treatment.Enhanced task-related activation of DLPFC following antidepressant treatment has alsobeen reported.136,334

A decreased correlation between activity in the broader ACC and the amygdala at rest andduring exposure to neutral, negatively valenced, and positively valenced pictures has beenreported in MDD.245 After 6 weeks of treatment with the SSRI sertraline (Zoloft), the sameMDD sample displayed an increase in ACC-limbic connectivity in the resting state andduring exposure to neutral and positive, but not to negative, pictures.245 In contrast, reducedfunctional coupling of the medial and ventral PFC with the amygdala observed in MDDduring exposure to sad faces was ameliorated by 8weeks of treatment with fluoxetine.224

Finally, studies using repetitive transcranial magnetic stimulation (rTMS) indicated thathigh-frequency rTMS inhibited negative bias in depressed individuals.335,336

4.1.2. Social Cognition

Antidepressant therapy may normalize patterns of neuronal responding to affective facialstimuli. For example, a study by Fu and colleagues121 examined the response to positivestimuli in patients withMDD comparedwith matched controls and found reduced activationin the basal ganglia, hippocampus, and extrastriatal regions among acutely ill patients withMDD; this pattern was attenuated following treatment with fluoxetine. Similarly, Keedwelland colleagues226 found that severely depressed patients showed increased visual cortexresponses to sad faces and reduced visual cortex responses to happy faces in the early stagesof antidepressant treatment. Following continued antidepressant therapy and clinicalimprovement, these patterns were reversed. Similarly, Victor and colleagues found that exag-gerated amygdala responses to masked sad faces and reduced amygdala activity to masked


happy faces were reversed following 4weeks treatment with sertraline.337 Moreover, inkeeping with previous findings demonstrating subgenual cingulate activity as a marker oftreatment response,259,338 further analysis of data from the study by Keedwell andcolleagues226 showed that increased activity in the right visual cortex and subgenual cingu-late to sad but not happy facial expressions in the first few weeks of treatment were predic-tive of a greater clinical recovery. In contrast, enhanced responses to happy and sad stimuli inthe ventrolateral prefrontal cortex were associated with a poor clinical outcome. These find-ings indicate that the negative bias toward sad faces improves and a positive bias towardhappy faces emerges with antidepressant treatment. Similarly, administration of erythropoi-etin, a potential candidate treatment for psychiatric disorders339 that exerts neurotrophic andneurorestorative effects, reduced neural responses in the amygdala and hippocampus tofearful compared with happy faces.339

A study by Lisiecka and colleagues examined the connectivity of the OFC, a key region inthe emotion regulation circuit, to other brain areas in patients with MDD.340 Lisiecka andcolleagues found that during a facial emotion identification task, responders to the antide-pressants mirtazapine (Remeron) and venlafaxine (Effexor) were characterized by increasedfunctional coupling between the OFC and motor areas that was evident at baseline. Themagnitude of response to antidepressant treatment also positively correlated with functionalcoupling between the left OFC and the caudate and thalamus. In contrast, increased connec-tivity between the OFC and the cerebellum was associated with nonresponse to antidepres-sant treatment.

Taken together, these results suggest that conventional antidepressants and novel treat-ments may dampen hyperactive responses to negative stimuli and enhance the salience ofpositive stimuli and that these changes may precede and predict changes in mood measuredby clinical rating scales.107

4.2. PET

It has been proposed that enhanced 5-HT transmission in MDD can compensate for abnor-malities in the density and sensitivity of certain 5-HT receptor subtypes, and this hypothesisis supported by evidence from postmortem, neuroimaging, and pharmacological challengestudies of depression.341 For example, in PET studies reduced 5-HT1A receptor binding inMDD has been reported by Drevets and colleagues, and this is reversed by chronic treatmentwith an antidepressant.268 Furthermore, half of the remitted patients who were unmedicatedor treated with SSRIs have been reported to experience depressive relapse after tryptophandepletion.342

4.3. Glutamate

The glutamatergic system was first implicated in mood disorders when D-cycloserine,a partial agonist at the N-methyl-D-aspartate (NMDA) receptor glycine site and an antag-onist at higher doses, showed antidepressant-like properties.343 Several other medicationswith glutamatergic activity have subsequently been studied for their antidepressantproperties. One drug of particular interest is ketamine (Ketanest), a noncompetitive

5.0. USE OF NEUROIMAGING IN BIOMARKER IDENTIFICATION AND EARLY DRUG DISCOVERY 369

NMDA antagonist, which has been shown to have antidepressant effects after a singleintravenous infusion in a number of double-blind, placebo-controlled studies.344,345

A study by Deakin and colleagues examined the cognitive effects of a novel low-trappingNMDA channel blocker, AZD6765, compared with ketamine in a pharmacological MRIstudy in untreated MDD.346 Both AZD6765 and ketamine increased sgACC activityand these changes correlated with improvement in depression ratings 24 h and 7 dayspostinfusion.

Elevated serum and plasma glutamate levels were significantly reduced after antidepres-sant treatment.347 Reduced Glx levels in the DLPFC and ACC have also been shown tonormalize after successful ECT therapy in patients with treatment-resistant depression.293,294

Responders to rTMS in one trial showed lower baseline glutamate concentrations in the leftDLPFC that increased in a dose-dependent fashion after exposure to therapy.348 Therapeuticsleep deprivation also increased Glx and glutamine in the same brain area in maleresponders with MDD and in responders with melancholic depression.349

5.0. USE OF NEUROIMAGING IN BIOMARKER IDENTIFICATIONAND EARLY DRUG DISCOVERY

Neuroimaging has utility at several levels in the drug discovery and development process:

(1) In characterizing preclinical models;(2) In early clinical studies to show that target engagement by a novel compound induces the

biological change(s) predicted to give clinical benefit;(3) In clinical trials to demonstrate proof of concept (PoC) or, in other words, that engaging

a particular target is linked to a meaningful change in a clinical endpoint and therebydemonstrating the effectiveness of the compound being tested.350,351

Neuroimaging provides a valuable opportunity to image healthy and disordered brainstructure and function in vivo. As such, it can help to identify biomarkers for drug devel-opment, measure drug efficacy and potentially predict treatment response. A biomarker isdefined as a response that can be objectively measured and evaluated as an indicator ofnormal or abnormal biological processes, or as an indicator of pharmacological responsesto a therapeutic intervention.350 The National Institutes of Health Biomarkers and Surro-gate Endpoint Working Group has defined three levels of biomarkers: Type 0 are used totrack the natural course of a disease; Type 1 can be used to examine the effects of interven-tion together with the known mechanism of action of a test compound but without a strictrelationship to clinical outcome; and surrogate endpoint Type 2 biomarkers are predictiveof clinical outcome.351 At present, most imaging methods in psychiatry do not meetbiomarker status. Some, however, may be considered as emerging biomarkers or prebio-markers because they enable the identification of therapy-relevant characteristics ofa disease.

In general, neuroimaging has potential utility in a number of the steps required to deter-mine the properties of a candidate compound including the comparison of its pharmacoki-netic and pharmacodynamic properties.


5.1. Role of Various Neuroimaging Modalities in Drug Development forDepression

5.1.1. PET

PET has been successfully used to explore a number of neurotransmitter systems, in partic-ular the serotonin and DA systems for which specific radioligands have been developed. Forexample, presynaptic DA synthesis and storage have been studied with 18F-fluorodopa; post-synaptic D1 and D5 receptor binding has been studied with 11C-NNC 112; and striatal post-synaptic D2, D3, and D4 receptor binding has been measured with 11C-raclopride.352

The most commonly used PET tracers for studying 5-HT function include 11C-WAY-1000635 (5-HT1A)

353 and 11C-MCN5652 (5-HTT).354

PET has been used for a variety of applications in drug development, for instance, byusing established or newly developed PET radiotracers to characterize a particular target.In addition, PET has been used to determine the degree of target engagement needed to exerttherapeutic effects. In addition, PET can be used to study the effect of a novel compound onan enzyme or a second messenger system.350

Two major approaches have been used in PET drug development for depression:

(1) To radiolabel a novel compound;(2) To use a tracer ligand to estimate the target occupancy of a novel compound.

If a novel compound is radiolabeled, important characteristics can be determined, such asbrain distribution, washout characteristics, and whether the compound is a substrate forbloodebrain barrier pumps. Depending on the nature of the radiolabel, studies can becarried out both in experimental animals and in humans with potentially less stringentrequirements for GMP (i.e. good manufacturing practice) material and preclinical safetydata due to the use of microdosing.355 When studying dosing for antidepressants, SSRIshave been shown to occupy � 80% of the serotonin transporter binding sites (SERTs) atclinically used doses; within this class of drugs, occupancy appears to be independent ofthe specific SSRI examined. However, the tricyclic antidepressant (TCA) clomipramine hasbeen reported to occupy 80% of the SERTat doses as low as 10mg, at a plasma concentrationof 1.42 ng/mL.356 However, clinically used doses of clomipramine are 50e150mg/day andtherapeutic plasma concentrations range between 175 and 450 ng/mL.357 This apparentdiscrepancy raises some obvious questions: For example, is SERT blockade not the onlymechanism by which clomipramine (and other TCAs) act? Alternatively, is the noradrenaline(norepinephrine) transporter also responsible for the therapeutic action of clomipramine(and of other TCAs), at least in part? Further, it appears likely that TCAs act differentlyfrom SSRIs due to their broad pharmacological actions at many different molecular targets.351

In other studies using PET, abnormal serotonin receptor distributions in MDD have beendiscovered that may help to develop new drugs that target specific receptor subtypes. Forinstance, 5-HT1A receptors are reportedly downregulated in the raphe nuclei, medial temporallobe, andmPFC indepression.267 In addition, serotonin transporter binding is altered inMDD.85

5.1.2. fMRI

A functional approach such as fMRI provides a systems neuroscience evaluation of thecircuitry that may underlie the behavioral effects of a drug, independent of its specific


biochemical mechanism of action.358 Many CNS drugs have multiple mechanisms of actionand can vary in efficacy across CNS targets with which they interact. fMRI monitors thecombined or integrated effect of these interactions across multiple systems and therebyreflects activity of the neural circuitry that drives behavior.358 fMRI can serve as a bridgebetween preclinical and subsequent clinical testing and evaluation.359 Both awake animalsand humans can be assessed using fMRI during rest and the performance of tasks, therebyproviding information about neural circuit activity in response to specific, reproducibleand well-characterized stimuli that can serve as a fingerprint of specific function.358 WhilefMRI is much more widely used than PET for the study of cognition, to date it has notbeen used as extensively as PET in drug development. However, fMRI is becoming increas-ingly used to identify and translate biomarkers from preclinical to clinical studies and viceversa (translation and reverse translation) in the characterization of novel compounds.fMRI studies can be useful in drug development in the following areas:

(1) Relating molecular targets to behavior;(2) Enrichment of study populations with treatment responders;(3) Differentiation of strong placebo responders;(4) Identification of pharmacodynamic markers;(5) Identification of potentially more sensitive measures of treatment response.

For example, hyperactivity of the default mode network has been reported in MDD andthis has been proposed to be a valuable biomarker for the illness.360


In terms of predictors and biomarkers, EEG has obvious advantages as it is widely avail-able and has a relatively low cost (compared to neuroimaging). A number of pretreatmentEEG parameters have been shown to differentiate responders and nonresponders and topredict treatment response to antidepressants.17

5.1.3.1. ELECTROENCEPHALOGRAPHY ALPHA BAND ACTIVITY

Ulrich and colleagues reported differences between MDD patient responders and nonre-sponders after 4 weeks of treatment with TCAs. Responders showed left lateralization ofalpha power at baseline and decreases in alpha power from baseline to week 4. Ina follow-up study, early changes in alpha band EEG after the first TCA dose were associatedwith treatment response at 3 weeks.361,362 Similarly, Knott and colleagues363 showed thatimipramine responders had increased alpha power compared to nonresponders at baseline,although this did not reach significance. A similar result was observed in paroxetineresponders compared to nonresponders.364

In a study by Bruder and colleagues,365 EEG alpha asymmetry between brain hemispheresrecorded at baseline was shown to differentiate SSRI antidepressant treatment respondersand nonresponders. Nonresponders showed greater activation (less alpha) over the righthemisphere, but responders did not. This result has been replicated by the same group.366

5.1.3.2. ELECTROENCEPHALOGRAPHY THETA ACTIVITY

Changes in frontal EEG measures in the theta band have been interpreted as reflectingaltered activity in the anterior cingulate regions implicated in emotional regulation.367 This


is the same area that Mayberg and colleagues proposed to be associated with predicting treat-ment response.259

Alterations in theta activity in MDD have been shown in association with treatment witha range of antidepressants363,364 and with ECT,368 although findings are inconsistent. Onestudy reported that lower theta baseline activity predicted response to imipramine andanother study reported that greater theta activity differentiated paroxetine respondersfrom nonresponders.364 In another study, frontal theta band relative power at baseline andat week 1 was a significant predictor of treatment response. Baseline relative theta powerwas lower in treatment responders, predicting treatment response at 8 weeks with an accu-racy of 63%. After 1 week of treatment, relative theta power predicted treatment responsewith 60% accuracy.369

5.1.3.3. ANTIDEPRESSANT TREATMENT RESPONSE INDEX

The antidepressant treatment response index (ATR) is a nonlinear combination of threefeatures: relative combined theta and alpha power (3e12 Hz), plus alpha power in twodifferent alpha bands (8.5e12 Hz and 9e11.5 Hz). The ATR index is defined as a probabilityscore ranging from 0 (low probability of response to treatment) to 100 (high probability ofresponse).17

An initial study reported that the ATR index predicted treatment response with an accu-racy of 70%.369 A large multicenter study (BRITE-MD) then tested this hypothesis on 220patients treated with escitalopram (Cipralex) or bupropion (Wellbutrin). All patients startedtreatment with escitalopram and 1week later continued with escitalopram, switched tobupropion, or were augmented with bupropion.370,371 Overall, ATR predicted both remissionand response with 70% accuracy. The other important question addressed by BRITE-MDwaswhether participants who are unresponsive to an initial antidepressant treatment should beswitched to a different agent or whether they would also respond poorly to other treatments.ATR was useful for predicting differential responses to either escitalopram or bupropionmonotherapy. Subjects with high ATR values were more than 2.4 times as likely to respondto escitalopram as those with low ATR values.370 Subjects with ATR values below thethreshold who were switched to bupropion were 1.9 times as likely to respond to bupropionalone than those who remained on escitalopram treatment. It is possible that if these resultsare replicated they could help to guide treatment decision making, i.e. continuing orchanging an antidepressant treatment after only 1 week rather than after the standard4e6weeks.17

5.1.3.4. THETA QUANTITATIVE ELECTROENCEPHALOGRAPHY CORDANCE

Cordance is a measure that combines EEG absolute and relative power according toa specific formula.372 It has been claimed that a decrease in prefrontal theta cordance at1 week after starting medication was a significant predictor of antidepressantresponse79,373e375 with overall accuracy ranging from 72% to 88%.17

5.1.3.5. EVENT-RELATED POTENTIALS

ERPs measure voltage changes on the scalp surface that correspond to cortical or brainstem activity in response to sensory stimuli (e.g. sound or light). P300, the wave recorded300ms after the presentation of an auditory stimulus, is interpreted as an ERP index of early


attention switching.376 Bruder and colleagues recorded P300 waves during dichotic listeningtests and showed that treatment response in patients with MDD was associated with higheramplitude of the P300 wave only at occipital electrodes.377 Another study reported thatelderly MDD nonresponders had a longer P300 latency at baseline.378

Another ERP tested in MDD is the loudness dependence of the auditory evokedpotential (LDAEP), which describes how one ERP component (N1/P2), generated inthe auditory cortex, changes with increasing loudness of the auditory stimulus. TheLDAEP is believed to correspond to the magnitude of serotonergic neurotransmission,particularly in the primary auditory cortex.379,380 It has been suggested that LDAEPmay be a differential marker of response for antidepressant drugs with serotonergicversus nonserotonergic mechanisms of action17. Stronger LDAEP slopes at baseline arereported to predict a response to citalopram (Celexa) and paroxetine (Paxil),381e383

whereas responders to reboxetine (Edronax) and bupropion are reported to have weakLDAEP slopes.382,384

5.1.4. Biomarkers from MRS

5.1.4.1. N-ACETYLASPARTATE

After successful ECT and/or antidepressant treatment, normal levels of NAA in theACC,291 basal ganglia,298 amygdala,296 and thalamus298 were reported. Interestingly, lowerpretreatment NAA levels in the ACC291 and hippocampus327 were associated with a greatertreatment response to ECT and antidepressants, and this may in turn predict clinicaloutcome.

5.1.4.2. GLUTAMIX

Reduced Glx levels in the ACC, amygdala, and DLPFC in MDD patients were normalizedafter successful ECT treatment in treatment-resistant depression.293,294,296 In addition,reduced glutamate levels in the VMPFC and ACC were only observed in chronic and recur-rent depression and correlated with illness duration.291,292

5.1.4.3. GABA

It has been reported that patients with treatment-resistant depression had lowest GABAlevels in the OCC,320 which increased with successful ECT treatment.321 Similar resultswere reported after 2months of SSRI treatment.322 Increased GABA levels after multipleECT sessions have also been reported in animal models and this is consistent with the estab-lished anticonvulsant effects of ECT.28 Moreover, Bajbouj and colleagues examined changesin cortical inhibitory measures in patients after 10 sessions of right unilateral ECT. After thefinal session of ECT, the mean cortical silent period increased significantly compared tobaseline,385 suggesting that the GABAergic system is enhanced with multiple ECT treat-ments. Treatment with low-frequency (1 Hz or less) rTMS is known to increase cortical inhi-bition and GABAergic functioning.386 Other work examining the inhibitory effects of variousrTMS frequencies indicated that both low- (1 Hz) and high- (10 or 20 Hz) frequency stimula-tion increased the duration of the cortical silent period in healthy subjects, indicating poten-tiation of GABAA functioning. It has been proposed that this may be partly due topresynaptic GABAB receptor inhibition of GABA release.387 This suggests that the thera-peutic effects of rTMS may be partially mediated through enhancement of GABAergic


inhibitory neurotransmission. Finally, a reduction in GABA levels in the PFC has also beenreported in MDD.323

5.2. Identification of Specific Regional Biomarkers in the Brain Using FMRI,PET, and Electroencephalography

5.2.1. Amygdala

fMRI has been used to identify biomarkers in the study of depression and to improve thechances of success in the development of novel treatments. The SSRI antidepressant citalo-pram reduced amygdala activation in response to fearful faces in healthy volunteers.388

The amygdala response to fearful stimuli has been proposed as a potential biomarker for anti-depressant effects.389 Indeed, given sufficient evidence from fMRI studies, hyperactivity inthe amygdala to negative stimuli in MDD patients could be translated into a valuablebiomarker, as successful antidepressant treatment has been shown to decrease thisresponse.118,134 Interestingly, a study comparing a novel low-trapping NMDA channelblocker, AZD6765, with ketamine in untreated MDD reported that both drugs reduce amyg-dala responses to fear and sadness in an emotional faces task 24 h postinfusion.346 Antide-pressants have also been found to normalize anomalies in resting activity in theamygdala.158 Furthermore, it has been reported that greater amygdala activation to emotionalfacial expressions in MDD patients at baseline predicts symptom reduction 8months later.391

The associations between elevated amygdala activity, depressive symptoms, plasmacortisol,392 and rapid eye movement sleep393 support the plausibility of this potentialbiomarker for MDD.

5.2.2. Hypoactive Prefrontal Cortex

Corticolimbic dysfunction with hyperactive limbic and hypoactive prefrontal regions hasbeen repeatedly reported in MDD patients, and can be reversed by antidepressant treat-ment.134 This has been replicated in a study using PET.136 Resting hypoactivation in DLPFChas long been a recognized concomitant of depression and this resting hypoactivity appearsto return toward normal levels with antidepressant treatment. Enhanced task-related activa-tion of DLPFC has also been reported following antidepressant treatment.136,334

5.2.3. Subgenual Cingulate Cortex

Imaging studies that assessed sgACC activity have indicated increased resting glucosemetabolism or BOLD activity in the sgACC. In addition, Greicius and colleagues240 con-ducted a resting state connectivity analysis of MDD patients and suggested that thealtered pattern of resting state connectivity in MDD is driven primarily by elevatedactivity of the sgACC. In line with these data, sgACC metabolism and CBF were reportedto be higher in the depressed, unmedicated phase versus the remitted phase of MDDpatients. Elevated sgACC BOLD activity has also been observed in MDD patients per-forming the stop-signal test394 and an emotional interference task.134 Consistent withobservations that experimentally induced sadness increases blood flow to the sgACC,the severity of depressive symptoms in MDD was found to correlate with glucosemetabolism in this region. Moreover, various treatment paradigms, including antide-pressant treatment,227,395 ECT,338 and deep brain stimulation of the sgACC,396 result

6.0. BEHAVIORAL CORRELATES AND USE OF NEUROIMAGING BIOMARKERS IN MODELS OF DEPRESSION 375

in decreased activity of the sgACC. In addition, fMRI studies have suggested that base-line hyperactivity in this region predicts treatment response in acutely depressedpatients.259,397

Pizzagalli and colleagues398 reported that resting rACC activity in the theta EEG bandcorrelates with treatment response after 4 months on nortriptyline (Aventyl) measuredusing the Beck Depression Inventory). Using the same low-resolution electromagnetictomography analysis (LORETA; a 3D EEG source localization method) technique, Mulertand colleagues reported that in a group of 20 MDD patients treated with citalopram orreboxetine, treatment response was associated with increased pretreatment resting thetaactivity in the rACC.383 Pretreatment EEG LORETA revealed higher resting theta activity(current density) in the rACC and OFC in responders to medication (fluoxetine or venla-faxine) in separate studies. Responders to placebo did not differ from nonresponders onthis metric. These EEG LORETA results add to a large body of neuroimaging evidencecorrelating pretreatment increased rACC activity with treatment response.259,397 Inaddition, the LORETA results383,397,399 suggest that the link between increased restingrACC theta activity and treatment response may generalize across antidepressant drugclasses.

A study using MEG reported that healthy controls showed a decrease in neuromagneticactivity in rACC across repeated exposures to fearful faces, whereas MDD patients showedan increased activity in the rACC.400 This increase correlated with an antidepressantresponse to ketamine, suggesting that it may be a possible biomarker. In addition, duringan n-back task401 decreased rACC activity was shown to correlate with the ketamineresponse. Taken together, high rACC in response to emotional faces but low rACC activityto cognitive demand appears to predict treatment response. In addition, subjects withlower source coherence between rACC and amygdala were most likely to respond toketamine.

6.0. BEHAVIORAL CORRELATES AND USE OF NEUROIMAGINGBIOMARKERS IN MODELS OF DEPRESSION

6.1. Theories of Human Major Depressive Disorder

6.1.1. Monoamine Hypothesis

The monoamine hypothesis is that depression is caused by underactivity of brain mono-amine neurotransmitters such as DA, noradrenaline (norepinephrine), and serotonin. Inthe 1950s monoamine oxidase inhibitors (MAOIs) and TCAs were serendipitously discov-ered to be effective in the treatment of depression.402e404 These findings and other support-ing evidence prompted Schildkraut to propose the ‘Catecholamine Hypothesis of AffectiveDisorders.405 Schildkraut proposed that ‘the biological basis of depression is a deficiency ofbrain catecholamine and serotonin systems and that ameliorating this neuronal deficiencywith an antidepressant would restore normal function in patients with MDD.’ The mono-amine hypothesis has been a major focus of research in depression for over 30 years andhas led to the development of new classes of antidepressant drugs, such as SSRIs, selectivenoradrenergic reuptake inhibitors (SNRIs), and selective and reversible MAOIs.404


According to the monoamine hypothesis, the therapeutic action of antidepressants is medi-ated by one of two mechanisms:

(1) Enhancement of monoaminergic neurotransmission by increased synaptic levels of DA,noradrenaline and serotonin;

(2) Specific agonist effects on serotonin, DA, or noradrenaline receptors.406

The monoamine systems in the brain have complex interactions with other neurotrans-mitter systems. Furthermore, there appears to be a mismatch in the timing of the effects ofantidepressants on brain monoamines and their therapeutic actions. Thus, antidepressantdrugs increase synaptic levels of monoamines within 24 h but their therapeutic effects arenot evident until at least 4e6weeks of drug treatment.407,408 Similarly, a significant propor-tion of patients with MDD are resistant to monoaminergic antidepressant therapies (seeSection 6.1.2). Therefore, the current prevalent view is that the monoamine hypothesismay only partially explain MDD and the response to antidepressant drugs.409e413 Neverthe-less, monoamine depletion has been useful as a model to investigate MDD and antidepres-sant mechanisms, and a number of such approaches are considered below.

6.1.1.1. TRYPTOPHAN DEPLETION

Evidence from biochemical challenge, imaging, and postmortem studies has associatedMDD with reduced function of central serotonergic systems.261,414e416 Tryptophan depletionhas been a useful approach to investigate the relationship between serotonergic function anddepression. This model assesses mood changes in response to serotonin depletion, achievedby consumption of an imbalanced amino acid mixture consisting of all essential amino acidsexcept for the dietary 5-HT precursor, tryptophan.417 The transient reduction in plasma tryp-tophan concentrations and brain 5-HT synthesis and concentrations, resulting from this die-tary manipulation induces symptoms of depression in remitted depressed patients who areeither off medication417 or being treated with antidepressants.418 In addition, tryptophandepletion also reverses the effects of light therapy in patients with seasonal affectivedisorder.419

Symptoms induced by tryptophan depletion show a relatively high specificity for MDD420

and seem to be heritable. Thus, in remitted depressed patients polymorphism in thepromoter (also known as the 5-HTT-linked polymorphic region; 5-HTTLPR) of the long (l)allele of the sodium-dependent serotonin transporter gene (SLC6A4 or 5HTT) predicted responseto tryptophan depletion,421 while in healthy women the short (s) allele of this functional poly-morphism and a positive family history of depression represented additive risk factors fortryptophan depletion-induced symptoms of depression.422 In addition, healthy subjectswith a family history of depression were shown to experience depressed mood symptomsfollowing tryptophan depletion, and this effect was smaller than in remitted depressedpatients but distinct from subjects without familial risk who showed no mood changesfollowing tryptophan depletion.423

In vulnerable individuals, acute depletion of tryptophan induces mood-congruentmemory bias and impairs memory consolidation.424 Similarly, in healthy volunteers acutedepletion of tryptophan alters reward-related behaviors425,426 and significantly impairs therecognition of fearful facial expressions in females, but not in males.427 Severe acute serotonindepletion leads to biological changes associated with MDD, including enhanced


noradrenaline (norepinephrine) transporter mRNA levels and reduced serotonin transportermRNA levels,428 an increased number of mineralocorticoid receptor binding sites,429 andaltered BDNF (brain-derived neurotrophic factor) gene expression in the dentate gyrus.430 Thesechanges are comparable to the mood and biological changes that occur in MDD.

Tryptophan depletion is associated with increased regional cerebral metabolic rates forglucose (rCMRGlu) in the OFC, ACC and ventral striatum. Abnormal CBF and glucose meta-bolic rate in these areas, as well as in the amygdala and hippocampus, have also beendescribed in medicated patients with recurrent MDD during tryptophan depletion and inpatients with MDD during spontaneous episodes of MDD. Although there is a growingconsensus that this corticostriatolimbic circuit is involved in MDD, not all regions arereported in all studies, and there is considerable variability in the direction of CBF andrCMRGlu changes.85

6.1.1.2. CATECHOLAMINE DEPLETION

MDD has been associated with noradrenergic and dopaminergic dysfunction (see Section6.1.1 above). Catecholaminergic dysfunction has been implicated in the pathophysiology ofdepression by studies of neurotransmitter synthesis and storage, which show that reductionof catecholamine stores exacerbates depressive symptoms.431

Lowered catecholamine brain function can be investigated experimentally in two ways:blockade of catecholamine synthesis by administration of alpha-methyl-para-tyrosine(AMPT) or dietary restriction of the immediate precursors phenylalanine and tyrosine: i.e.acute phenylalanine/tyrosine depletion (APTD).

6.1.1.2.1. AMPT DEPLETION Mood responses to AMPT depletion in healthy subjects areusually not significant.432 The presence of depressive symptoms induced by catecholaminedepletion in unmedicated remitted patients with MDD suggests state independence of thisbiological marker.433 The depressive symptoms evoked by catecholamine depletion are oftensimilar to those experienced by patients during a depressive episode, suggesting clinicalplausibility.170 However, catecholamine depletion failed to exacerbate depression inuntreated, symptomatic depressed patients prior to initiation of antidepressant therapy.434

This finding may be due to brain catecholamine function being maximally dysfunctionalin symptomatic depressed patients (a ceiling effect).435 Catecholamine depletion reversedthe therapeutic effects of antidepressants in treated depressed patients, particularly theeffects of catecholamine reuptake inhibitors.434 Catecholamine depletion also reversed theeffects of light therapy in patients with seasonal affective disorder.419

The return of depressive symptoms following catecholamine depletion has been associ-ated with decreased brain metabolism in the OFC and DLPFC. Similarly, increased restingmetabolism in the prefrontal cortex and limbic areas has been found to increase vulnerabilityto catecholamine depletion-induced exacerbation of depressive symptoms.436

AMPT impaired attention, but not psychomotor speed, in a D2 ligand-binding PET study,using 11C-raclopride in healthy volunteers.437 Impaired attention induced by AMPT wasassociated with increased raclopride binding.437 This study has the limitation that it didnot include a placebo condition, but nevertheless suggests that the effects of AMPTon cogni-tive performance may be associated with lowered DA function.438 Interestingly, decreasedperformance on memory and attention tasks relative to placebo was reported when AMPT


was followed by 40 h sleep deprivation, but there were no significant effects after AMPT orsleep deprivation alone.439

6.1.1.2.2. ACUTE PHENYLALANINE/TYROSINE DEPLETION In healthy individuals, APTD(like AMPT) does not induce depressive symptoms. A meta-analysis of APTD studies foundthat self-report ratings of depressed mood are unaffected by APTD, except when it is fol-lowed by a public speaking task.438

APTD reduces the psychostimulant effects of amphetamine (indicated by self-report andcognitive tests).440,441 In addition, cognitive processes are affected by APTD, and it has beensuggested that APTD specifically interferes with spatial short-term and working memory buthas no effect on sustained attention or other memory processes.442,443 However, it has alsobeen reported that APTD impaired the retrieval of words from long-term memory, whereasattention and memory for abstract figures were unchanged.444

Nathan and colleagues compared the cognitive effects of acute tyrosine depletion andAPTD in a double-blind, placebo-controlled crossover study in healthy volunteers. Acutetyrosine depletion selectively impaired memory consolidation, whereas APTD selectivelyimpaired working memory performance.445 A pilot PET study found that APTD did notinduce changes in D2 receptor binding.446 Prolactin levels are increased after APTD,441,443

which is indicative of reduced central DA receptor function. In contrast, levels of melatoninand IL-6 (interleukin-6) were unaffected by APTD.447,448 Finally, in a study of euthymicsubjects with a history of major depression, APTD attenuated DA function, reflected byincreased plasma prolactin levels, and decreased spatial memory performance.449 However,ratings of depression were unaffected, suggesting that disruption of dopaminergic functionby APTD (unlike disruption of serotonergic function by tryptophan depletion) does notinduce a lowering of mood in individuals who are vulnerable to depression.

6.1.2. Glutamate Hypothesis

A considerable body of evidence suggests that brain glutamate systems may be involvedin the pathophysiology of MDD and in the mechanism of action of antidepressants.408,450e455

Although almost all current antidepressant drugs (e.g. TCAs, SSRIs and SNRIs) have theirmajor action(s) on brain monoaminergic neurotransmitter mechanisms (see above), theirdelayed onset of action (generally at least 4e6weeks is required for significant symptomrelief) suggests that other processes are involved in the mediation of their therapeuticeffects.408,455 Furthermore, a significant proportion of MDD patients do not achieve remissionfollowing treatment with standard monoaminergic therapies and are termed treatment resis-tant. Thus, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, con-ducted in a large adult outpatient treatment-seeking sample with MDD (n¼ 3671), foundthat only 36.8% of patients achieved remission following an optimized trial of the SSRI cita-lopram for up to 12 weeks.456,457 Remission in half of the patients often required 6months oftreatment and two antidepressant trials.456,457

The role of glutamate in synaptic plasticity and adaptive processes in the brain coupledwith the discovery of the rapid-onset antidepressant effects of the noncompetitive NMDAantagonist, ketamine, have prompted a renewed interest in the glutamate theory of depres-sion and the development of novel glutamate antagonists as therapeuticagents.345,408,451e453,455,458,459 Indeed, it has been suggested that a paradigm shift from


a monoamine hypothesis of depression to a neuroplasticity hypothesis focused on glutamatemay represent a substantial advancement in the working hypothesis that drives research fornew drugs and therapies for MDD.454 In particular, it has been proposed that glutamateapproaches may help to address the two most challenging problems with current antidepres-sant therapies, namely slow onset of action and treatment resistance.454,455 Encouraginglyfor the glutamate hypothesis, antidepressant effects have now been reported in clinicalstudies with both ionotropic and metabotropic glutamate antagonists and further explor-atory and large-scale clinical trials are underway.458e463

In mechanistic studies of the glutamate hypothesis, Salvadore and colleagues used1H-MRS to investigate whether prefrontal levels of amino acid neurotransmitters predictthe antidepressant response to a single intravenous infusion of ketamine in MDD patients.464

Correlation analyses were conducted to determine whether pretreatment with GABA orglutamate, or the Glx:Glu ratio predicted change in depression symptoms after ketamineadministration. The pretreatment Glx:Glu ratio in the dorsomedial and dorsal anterolateralPFC negatively correlated with improvement in depressive symptoms suggesting an associ-ation between a lower Glx:Glu ratio and a greater improvement in response to ketaminetreatment.

The term glutamate-based depression (GBD) has been proposed by McCarthy andcolleagues.452 GBD is defined as a chronic depressive illness associated with environmentalstress and diseases associated with altered glutamate neurotransmission. It has beenproposed that glutamate-induced hyperactivation of NMDA receptors in the sgACC (Brod-mann area 25) plays an important role in the etiology of depression and may be responsiblefor the high incidence of comorbid depression associated with diseases with glutamateetiology.452 Supporting evidence for this hypothesis is the finding that a range of antidepres-sant treatments, including SSRIs, ketamine, ECT, and deep brain stimulation, have a damp-ening effect on sgACC activity over time courses that are consistent with their therapeuticeffects.390,396,452 In addition, a study showed that both the novel NMDA antagonistAZD6765 and ketamine increased sgACC activity and these changes correlated withimprovement in depression ratings 24 h and 7 days postinfusion.346

6.1.3. Neurotropic Theories

6.1.3.1. CYTOKINE HYPOTHESIS

In 1927,Wagner-Jaureggwon the Nobel Prize for the seminal observation that activation ofthe immune system by an infectious agent (i.e. malaria inoculation) can affect psychiatricfunctioning. He concluded that cytokines have an important signaling role and can serveas mediators between the immune system and the CNS. Maes and colleagues465,466 investi-gated plasma concentration and in vitro production of several cytokines, including IL-6and IL-1, and concluded that an increase in proinflammatory cytokines in patients withMDD appears to correlate with the severity of illness and measures of hypothalamic-pitui-tary-adrenal (HPA) hyperactivity. Cytokines have been reported to elicit depression, forexample IFN-a (interferon a)-induced depression in cancer patients was comparable tothat of patients with MDD.467 Interestingly, IFN-induced depression was associated withincreased psychomotor retardation, weight loss and significantly less severe feelings of guilt,suggesting that cytokines may preferentially target brain mechanisms that mediate psycho-motor responses, such as the basal ganglia.467 A meta-analysis of studies between 1967 and


2008 revealed that depression is often associated with an increase in proinflammatory cyto-kines [IL-1b, IL-6, TNF-a (tumor necrosis factor a), and IFN-g].468,469

Cytokines and other immune molecules can impact mood and cognition in part throughthe modulation of neuronal circuits and functioning. Plasticity is critical for mood, cognition,development and behavior throughout the lifespan.470 Cytokines and other immune factorsplay a key role in modulating early brain development as well as neuronal plasticity. Indeed,prolonged exposure to proinflammatory cytokines can impair neuronal plasticity, therebycontributing to cognition and mood disorders.471

The brain regionswith the highest concentrations of proinflammatory cytokines (specificallyIL-1b, IL-6, and TNF-a) include the cortex, hippocampus, and hypothalamus,472e475 areas thatare critical for antidepressant responses and cognitive function.470 Cytokines can contribute toHPA axis hyperactivity476 and also modulate 5-HT and DA systems,477e479 which may subse-quently lead to mood changes and the emergence of symptoms of depression.

Eisenberger and colleagues measured neural responses to social exclusion during a CyberBall passing game in healthy volunteers after acute administration of placebo or endotoxin. Itwas reported that an observed increase in IL-6 correlated with subjectively scored depressedmood. Interestingly, changes in brain regions that are involved in mediating responses topain, such as the anterior and posterior insula, and regions associated with changes inmood, such as the DMPFC, MPFC, and precuneus, were reported to correlate with IL-6 levelsin the endotoxin-treated group.480 Harrison and colleagues481 reported that inflammationcaused by administration of typhoid vaccine modulated neural activity in brain regions repre-senting internal bodily state. Another study using a face perception task showed that the func-tional connectivity between the sgACC and MPFC, NAc, amygdala, and superior temporalsulcus, negatively correlated with IL-6 levels caused by administration of typhoid vaccine inhealthy controls. Mood level was shown to decrease with IL-6 levels. These changes mightunderpin the marked decrease in social behavior associated with acute sickness, possiblyreflecting an internal self orientation of attentional focus.482 No studies have been performedwith depressed patients, but increased proinflammatory levels associated with depressionmight relate to social impairments that are reported in MDD.

6.1.3.2. BDNF HYPOTHESIS

An increasing body of evidence indicates that alterations of BDNF expression in limbicbrain regions may have a critical role in the pathophysiology and/or treatment ofMDD.483e485 BDNF is expressed abundantly in adult limbic brain structures and there arereports from preclinical studies that stress reduces BDNF-mediated signaling in the hippo-campus, whereas chronic treatment with antidepressants increases BDNF-mediatedsignaling.486 A study reported the unexpected finding that peripheral administration ofBDNF produces antidepressant-like effects in cellular and behavioral models.485 Takentogether, these data provide support for the BDNF hypothesis of depression, although conflict-ing findings exist (see below).

Clinical postmortemstudieshavedetecteddecreasedBDNFandTrkB (neurotrophic tyrosinekinase receptor type 2) expression in the hippocampus of suicide victims and increased levels inpatients treated with antidepressants before death. Furthermore, serum BDNF in depressedpatients is abnormally low, but can be restored followingpharmacological treatment.486 In addi-tion,Dias and colleagues reportedan increase inBDNFfollowing chronicECT, tranylcypromine


(Parnate), and desipramine (Norpramin) treatment.487 In contrast, following administration offluoxetine in rats, both downregulation of BDNF expression in the hippocampus488 or no effecton exon-specific BDNF transcript levels487 have been reported. These conflicting findings maybe due to species differences or could be specific to SSRIs.

Interestingly, a clinical study measured pre- and posttreatment serum BDNF levels inpatients with treatment-resistant depression treated with ECTor rTMS, and results suggestedthat ECT and rTMS may not exert their clinical effects by altering serum BDNF levels inpatients with treatment-resistant depression.489

The human BDNF gene is complex, comprising eight exons that provide multiple tran-scripts. Therefore, it has been proposed that differential regulation of BDNF transcripts bystress and antidepressant treatments may result in contrasting functional effects.486

Finally, a meta-analysis has indicated that serum BDNF levels are differentially regulatedby stress and antidepressants in MDD patients,490,491 suggesting that serum BDNF could bea useful biomarker for MDD and antidepressant efficacy, although further validation studiesare required.

6.1.3.3. HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

A consistent, characteristic feature of MDD reported in many studies is hyperactivity ofthe HPA axis. Severe depression is associated with hypersecretion of cortisol and with pitu-itary and adrenal gland enlargement.492 HPA abnormalities in MDD include increased secre-tion of cortisol, elevated basal CSF corticotrophin-releasing hormone levels, and increasedsize and activity of the pituitary and adrenal glands.493 Abnormal cortisol responses inMDD patients were reported to be independent of depressive state, suggesting that this isa state-independent marker.170 Depression-like alterations of PFC functions, such as inhibi-tory control, attentional regulation, and planning, following cortisol administration andthe bidirectional associations between amygdala activity and cortisol levels494 suggest clin-ical plausibility of cortisol-related endophenotypes for MDD.170

6.1.4. Neurodevelopmental TheoriesdGenetic Polymorphisms

Mental illness tends to run in families, strongly implicating genetic causation,495 andgenetic studies enable a better understanding of candidate genetic factors and functionalpathways that may underlie the pathophysiology of MDD. Genetic approaches combinedwith neuroimaging methods can be useful tools in identifying brain changes that may bemodulated by underlying genetic factors, and are integral to neural function, includingneuronal organization, neuronal signaling, and interneuronal communication.iv

ivFor further discussion regarding the use of neuroimaging to study the genetic basis of neuropsychiatric

disorders in human subjects and in animal models please refer to Tost et al. in Chapter 6, Rethinking

the Contribution of Neuroimaging to Translation in Schizophrenia; Steckler and Salvadore in Chapter 7,

Neuroimaging as a Translational Tool in Animal and Human Models of Schizophrenia; Westphal et al. in

Chapter 8, Functional Magnetic Resonance Imaging as a Biomarker for the Diagnosis, Progression, and

Treatment of Autistic Spectrum Disorders; Badura et al. in Chapter 9, Translational Neuroimaging for Drug

Discovery and Development in Autism Spectrum Disorders: Guidance from Clinical Imaging and Preclinical

Research; Schmidt et al. in Chapter 5, Positron Emission Tomography in Alzheimer Disease: Diagnosis and

Use as Biomarker Endpoints; and Novak and Einstein in Chapter 4, Structural Magnetic Resonance Imaging

as a Biomarker for the Diagnosis, Progression, and Treatment of Alzheimer Disease, in this volume.


Studies on the biological basis of depression have found stronger associations betweenspecific biological dysfunctions and certain components of major depression than with thepresence or absence of MDD, as defined by the Diagnostic and Statistical Manual of MentalDisorders, 4th Edition.147,170 Symptoms such as anhedonia, cognitive deficits, lowered mood,psychomotor retardation and rumination have been associated with specific focal abnormal-ities in CBF.136,158 It has been proposed that recurrence of depressive episodes has a highgenetic liability,496 while a high temporal stability of the phenotype is favorable for geneticstudies.

6.1.4.1. AMYGDALA HYPERACTIVITY

Significant differences have been reported between the s/s and l/l genotypes of theSLC6A4 (5HTT) gene promoter in the amygdala response to fearful faces in the absence ofbehavioral differences.497 The s allele was associated with increased amygdala activationin response to negatively valenced faces or decreased amygdala activation to neutralstimuli.217,497,498 Similar results have been reported using dot probe and emotionallyvalenced pictures498e500 and public speaking as stimuli.501 In addition, the s allele hasbeen associated with elevated baseline amygdala activity502 and reduced amygdala volumein healthy subjects.503,504 A PET study reported that during tryptophan depletion, MDDcarriers of the s allele showed reduced glucose metabolism of the left amygdala comparedwith l/l homozygotes.143 The impact of the SLC6A4 genotype on amygdala function hasalso been reported in studies with stressed rhesus monkeys505 and patients withMDD.505e507 However, a meta-analysis suggests that these effects are only marginallysignificant.508

The 5-HT1A receptor, encoded by the HTR1A gene, plays a critical role in serotonergicsignaling and has been implicated in MDD.267 It was reported that the G allele of a functionalsingle nucleotide polymorphism (SNP; rs6295) was associated with greater amygdala reac-tivity in response to emotionally valenced faces507 in a MDD sample and to threat-relatedstimuli and the level of trait anxiety in healthy individuals.509

The tryptophan hydroxylase 2 (TPH2) gene is another candidate for modulation of amygdalafunction. TPH2 is involved in the synthesis of neuronal 5-HT.217,510e512 Brown andcolleagues510 reported that the T allele of rs4570625 was associated with a greater amygdalaresponse to angry or fearful faces while Canli and colleagues217 found that the effect of thers4570625 variant on amygdala function extended to both positively and negatively valencedstimuli in healthy controls. In a subsequent study by Canli and colleagues,513 an additiveeffect of TPH2 and SLC6A4 polymorphisms was reported on amygdala reactivity that wasmost robust for sad or fearful faces: carriers of the t and s alleles displayed a 0.24% greaterBOLD response in the amygdala than subjects who did not possess either a t or an s allele.These data derive further support from a PET study,511 which showed that the TPH2 G allelepredicted a placebo-induced improvement in social anxiety that was associated with a reduc-tion in amygdala activity. In contrast, Lee and Ham512 reported that individuals homozygousfor the G allele of rs4570625 showed higher levels of amygdala activity in response to sad (butnot angry) faces than their counterparts who did not carry the G allele.

Polymorphisms of the BDNF,514 COMT (catechol-o-methyltransferase),515e517 and MAOA(monoamine oxidase A)518 genes have also been associated with differing degrees of amygdalareactivity in healthy controls and different patient groups.


6.1.4.2. ANHEDONIA

Anhedonia has been proposed to be a specific symptom of depression519 as, inschizophrenia,cf 147 anhedonia has been related to the depressive syndrome ratherthan the deficit syndrome of the disorder.520 Neurotropic factors, including CREB(cyclic AMP-responsive element-binding protein), BDNF, and the transcription factorfosB (or delta-FosB), may represent molecular mechanisms involved in long-term alter-ations of the brain reward system.521 Preliminary evidence for a potential heritabilityincludes a functional polymorphism of the COMT gene that has been associated withindividual variation in the response of the brain to dopaminergic challenge.522 Epidemi-ological research provides clues for state independence, heritability, and familial associ-ation of dysfunctions of the brain reward system as endophenotypes for MDD.170

6.1.4.3. SUBGENUAL ALTERATIONS

The serotonin transporter (5-HTTR) has been associated with elevated sgACC activity inunmedicated MDD.136,523 It has been reported that the s allele was associated with reducedleft middle frontal gyrus,523 pregenual503,523 and sgACC503 volumes. The reported associa-tion between reduced volume of BA9 and the short 5-HTTLPR allele524 is interesting becauseglial cell loss and a reduction in neuronal size postmortem has also been observed in thisregion in MDD.525

6.1.4.4. CORTICOLIMBIC DYSFUNCTION

A heuristic model of MDD is a loss of top-down PFC control over limbic regions, such asthe amygdala, leading to emotional, behavioral, cognitive, and endocrine changes character-istic of the disorder.85 The genetic basis of this abnormal PFC-limbic functional coupling is inthe early stage of investigation. It has been reported the s allele of the 5-HTTLPR polymor-phism was associated with reduced functional coupling between the supragenual ACCand the amygdala, but increased functional coupling between the VMPFC and the amygdalain healthy controls exposed to threatening faces.503 Additionally, the degree of functionalcoupling between the perigenual ACC and the amygdala predicted approximately 30% ofthe variance in scores on the harm avoidance subscale of the Temperament and PersonalityQuestionnaire.503 The greater VMPFCeamygdala coupling observed in the 5-HTTLPR sallele carriers replicated a report526 of a similar effect in healthy volunteers shown aversivepictures. Similarly, Dannlowski and colleagues223 reported that the inverse functional corre-lation between dorsal anterior cingulate cortex (dACC) and amygdala activity observed intheir healthy control sample was attenuated in carriers of the high-activity MAOA promoterpolymorphism alleles (3.5R or 4R). Further, MDD cases with high-activity MAOA variantsshowed the weakest amygdalaedACC coupling and the most severe course of illness.

6.1.4.5. SEROTONIN RECEPTORS

6.1.4.5.1. 5-HT1A RECEPTOR The first evidence for a functional genetic association ofa 5-HT receptor polymorphism with MDD was reported by Lemonde and colleagues.527

Their results suggested a molecular mechanism by which the single nucleotide C(-1019)Gpolymorphism may regulate HTR1A gene (which encodes 5-HT1A receptors) expression invivo by impairment of repression of the HTR1A promoter in presynaptic raphe neuronsleading to reduced serotonergic neurotransmission and potentially predisposing individuals


to MDD. Interestingly, the G(-1019) allele depresses presynaptic HTR1A transcription, butmay have the opposite effect of reducing NUDR (Nuclear deformed epidermal autoregula-tory factor 1 homologue)-enhanced HTR1A transcription in postsynaptic cells in regionssuch as the hippocampus and septum. The net effect of these changes would be a reductionin serotonergic neurotransmission.527 In patients with MDD the homozygous G(-1019) allelewas enriched twofold versus controls.527 These data have been independently replicated inanother MDD sample,528 as well as in elderly patients who became depressed after sufferinghip fractures529 and hepatitis C patients with IFN-induced depression.530 In a subsequentstudy by Lemonde and colleagues, patients with MDD with the homozygous G(-1019) geno-type were reported to be approximately twice as likely to be nonresponders to an antidepres-sant as those with the C(-1019)C genotype.531

6.1.4.5.2. 5-HTT Frokjaer and colleagues532 found that healthy individuals, who were athigh risk of developingMDD by virtue of having a twin with the disorder, displayed reduced5-HTT binding in the DLPFC and, to a lesser extent, the ACC. Nevertheless, given the natureof this study, it is unclear whether the reduction in 5-HTT binding is indicative of a geneticvulnerability to MDD or whether it reflects an adaptive compensation for impaired seroto-nergic function.

7.0. RECIPROCAL NATURE OF NEUROIMAGING RESULTSIN ANIMAL AND HUMAN MODELS OF DEPRESSION

In drug discovery research and development for MDD, using methods that can be trans-lated from preclinical to clinical platforms and vice versa facilitates the early identification ofpromising compounds to advance to late-stage clinical trials. Translational neuroimaging canprovide qualitative and quantitative information on brain morphology and function inpreclinical models, healthy participants and patients with MDD.v

Using different neuroimaging tools, potential biomarkers for depression have beendiscovered, the most promising of which have been identified using several independentmodalities. For example, hyperactivity of the sgACC in MDD and its reduction after antide-pressant, ECT, or rTMS treatment has been reported using EEG, fMRI, MEG, MEG and PETmethods.

7.1. Advances in Developing Drugs for Depression Through the Use ofNeuroimaging

Neuroimaging techniques have advanced rapidly and are playing an increasingly impor-tant role in understanding abnormal brain structure and function in MDD. Neuroimaging

vFor further discussion regarding the use of small animal imaging in bridging studies between preclinical

and clinical studies during CNS drug discovery and development, please refer to Ferris et al. in Chapter 3,

Small Animal Imaging as a Tool For Modeling CNS Disorders: Strengths and Weaknesses; Badura et al. in

Chapter 9, Translational Neuroimaging for Drug Discovery and Development in Autism Spectrum Disor-

ders: Guidance from Clinical Imaging and Preclinical Research; Steckler and Salvadore in Chapter 7, Neu-

roimaging as a Translational Tool in Animal and Human Models of Schizophrenia; and Schwarz et al. in

Chapter 11, Translational Neuroimaging: Substance Abuse Disorders, in this volume.

8.0. SUMMARY AND FUTURE PROSPECTS 385

approaches, in particular fMRI, are also being increasingly used in early drug developmentfrom preclinical studies to Phase I and Phase IIa clinical trials. Thus, fMRI can serve asa bridge between preclinical and clinical testing and evaluation.359 Responses in animalsand humans can be assessed using fMRI during rest and while performing a wide rangeof tasks, thereby providing information about neural circuits that are activated in responseto specific, reproducible, and well-characterized stimuli that can serve as fingerprints ofspecific functions.358 A disadvantage of the fMRI approach is that the data generated are indi-rect and qualitative rather than quantitative. Even though the BOLD response is recordedclose to neuronal activity (local field potentials), BOLD is a result of a combination of variousevents including CBF, CBV and oxygen metabolism. However, new approaches are beingdeveloped and tested in MRI to measure CBF. For example, ASL magnetically labels theblood, thereby creating a noninvasive endogenous contrast agent.533 ASL can be used toproduce a quantitative baseline measurement of CBF or images can be acquired over a periodof time to measure changes in CBF.

In comparison to fMRI, PET has the advantage of providing quantitative rather than qual-itative data. However, PET also has limitations as it is an expensive method, requires expo-sure to radiation, and the, often challenging, development of a selective high-affinityradioligand.

EEG and MEG measure neuronal activity with superior temporal resolution compared toPET and fMRI. Indeed, as current MEG systems use several hundred sensors; good spatialresolution can be obtained using this technique.

Thus, each neuroimaging tool has advantages and disadvantages but if combined canprovide complimentary measurement of neuronal information related to both healthy anddisordered function. Therefore, multimodal imaging is likely to be increasingly used infuture as, by combining different modalities, it may be possible to define common neuronalgenerators that will increase our understanding of MDD and thereby help to identifyimproved therapies for this disorder.

8.0. SUMMARY AND FUTURE PROSPECTS

MDD is a common and disabling disorder that is poorly treated by currently prescribeddrug therapies. Many patients with MDD do not respond to available antidepressant drugsand following a number of drug treatment cycle failures are termed treatment resistant.Patients that do respond to drug therapy generally experience significant side effects anda delay of 4e6weeks before a therapeutic benefit is observed. Indeed, often multiple4e6-week treatment cycles with different drugs are required to identify an effective therapy.Hence, there is a significant medical need for new drug therapies to treat MDD. However, thepoor predictive validity of the preclinical methods available to detect the potential efficacy ofnovel compounds and a lack of common endpoints between preclinical and clinical measureshave proven to be major limitations in drug development for MDD. Thus, preclinical andearly clinical studies with novel putative antidepressants have often identified promisingtrends that have not been confirmed by the results of subsequent large Phase III studies.Unfortunately, placebo-controlled trials are difficult to conduct in patients with the typeand degree of depression that most requires pharmacological intervention and high placeboresponse rates can confound detection of positive treatment effects.


Neuroimaging studies are providing important insights into our understanding of theneuroanatomical and neurochemical substrates of MDD. Many imaging methods such asfMRI and PET can be applied in animal species used for preclinical research in addition tobeing widely used in clinical studies. Consequently, neuroimaging approaches are becomingincreasingly valuable for drug discovery and development and the potential translation ofpreclinical promise to clinical therapeutic benefit.

Neuroimaging methods that have been routinely used to study MDD include MRI, fMRI,MRS, PET, EEG, and more recently MEG. Each method has advantages and disadvantages;for example PET can provide quantitative measurement of neurotransmitter receptor occu-pancy but requires the development of a high-affinity, selective radiotracer, which is oftenvery challenging. In contrast, BOLD fMRI signals can be recorded at rest (described as thedefault mode network) and in response to a wide range of stimuli and drugs, but the datagenerated are indirect and qualitative. Therefore, increasing numbers of clinical develop-ment programs are using different methods in parallel (e.g. fMRI and PET) or multimodalimaging approaches, such as the simultaneous acquisition of EEG and fMRI data.

A considerable body of evidence indicates that MDD is associated with blunted rewardresponsiveness, hypersensitivity to punishment, impaired learning and memory, impairedsocial cognition, and negative bias. These deficits were identified by extensive studies ofpatients with MDD in behavioral and cognitive tasks. Imaging studies using MRI, fMRI,and PET have identified a number of brain regions that are functionally and structurallyabnormal in MDD and which are implicated in mediating these cognitive deficits. Thesebrain regions include the ACC, amygdala, basal ganglia, hippocampus, OFC, PFC, sgACC,and thalamus. Similarly, in MRS and PET studies, MDD patients have been reported tohave reduced levels of neurotransmitter metabolites including GABA, glutamate, andNAA, and alterations in the density and/or affinity of neurotransmitter receptors and trans-porters, including a number of serotonin receptor subtypes. Some of these deficits have beenshown to reverse and/or normalize after successful antidepressant, ECT, and/or TMStreatment.

It is increasingly recognized that the introduction of imaging biomarkers is a potentiallysignificant step forward for drug development in MDD. Such studies bridge the gap betweenanimal and human studies and have the potential to accelerate clinical trials by providingrapid Go/No-Go decisions. Potential biomarkers for MDD that have been identified usingdifferent imaging methods (such as EEG, fMRI, and PET) include corticolimbic dysfunction,frontal asymmetry hyperactive amygdala, and hyperactive sgACC. These and otherbiomarkers (see above) have been used to investigate the neural substrates of MDD and toassess the potential efficacy of novel compounds in early-phase clinical trials.

Since the 1970s, the prevalent hypothesis of drug discovery and development for MDDhas been the monoamine hypothesis. This hypothesis arose from the serendipitous discoveryof the antidepressant properties of MAOIs and tricyclics, which subsequently led to thedevelopment of first-line antidepressant therapies such as SSRIs and SNRIs. As describedabove, these drug classes have significant limitations in terms of side effects, nonresponders,and a latency of 4e6weeks before the onset of their therapeutic action. However, thediscovery of the rapid-onset antidepressant properties of the NMDA receptor antagonist ket-amine together with new imaging approaches to drug discovery have directed interesttoward the brain glutamate system as a promising target for new treatments for MDD.

REFERENCES 387

Indeed, it has been suggested that glutamate-induced hyperactivation of NMDA receptors inthe sgACC area (BA25) plays an important role in the etiology of depression and may beresponsible for the high incidence of comorbid depression observed in diseases with gluta-mate etiology. This is an exciting example of convergent approaches to drug discovery anddevelopment, in which neuroimaging results combined with a novel therapeutic discoveryhas generated a new working hypothesis that has the potential to drive research for newdrug therapies for MDD.

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Translational Neuroimaging || Neuroimaging Approaches to the Understanding of Depression and the Identification of Novel Antidepressants